JPH11139975A - Type a monoamine oxidase inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject inhibitor having excellent type A monoamine oxidase-inhibiting action and exhibiting therapeutic or preventive effects on nervous diseases, especially depression. SOLUTION: This inhibitor contains an isoxazole derivative of formula I [R<1> is a 5 to 6-membered aromatic heterocycle having one or two hetero atoms selected from nitrogen, oxygen or 6-14C aryl; R<2> is hydrogen, a halogen or the like; R<3> is amino, a mono-1-6C alkylamine or the like; X is oxygen or sulfur; (n) is 2-6] or its salt as an active ingredient. 3-(2-Aminoethoxy)5-phenylisoxazole or the like is preferable as the compound of formula I. The compound of formula I is obtained by halogenating a compound of formula II, reacting the product with a compound of the formula HX-(CH2 )n R<3> a (R<3> a is a protected amino, a protected mono-1-6C alkylamino or the like), and as necessary, deprotecting the reaction product.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an isoxazole derivative having an excellent A-type monoamine oxidase inhibitory activity or a pharmacologically acceptable salt thereof as an active ingredient, which is used for depression, Parkinson's disease and Alzheimer's disease (Alzheimer's disease). The present invention relates to a therapeutic or preventive agent for neurological diseases (particularly depression) such as cerebrovascular dementia (cognitive impairment based on cerebrovascular dementia).

[0002]

2. Description of the Related Art Depression is a mood disorder in which mood suppression is the main symptom, and is considered to be one of the causes of dysfunction of the brain serotonin and noradrenaline nervous systems. Serotonin and noradrenaline are mainly decomposed and metabolized by type A monoamine oxidase among monoamine oxidases, and lose biological activity. A-type monoamine oxidase inhibitors are considered to be useful as antidepressants, and their research and development have been actively conducted. In recent years, moclobemide as a selective type A monoamine oxidase inhibitor has been clinically provided.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have conducted intensive studies over many years on the synthesis of isoxazole derivatives and their pharmacological actions with the aim of developing excellent therapeutic agents for depression and the like. The derivative has a potent A-type monoamine oxidase inhibitory action, such as depression, Parkinson's disease, Alzheimer's dementia (cognitive impairment based on Alzheimer's disease) or cerebrovascular dementia (cognitive impairment based on cerebrovascular dementia, etc.) The present inventors have found that they have a therapeutic effect or a preventive effect (particularly, a therapeutic effect) on a neurological disease (particularly, depression), and completed the present invention. The present invention
Provided is a monoamine oxidase inhibitor comprising an isoxazole derivative having excellent A-type monoamine oxidase inhibitory activity as an active ingredient.

[0004]

Means for Solving the Problems The active ingredient of the monoamine oxidase inhibitor of the present invention is an isoxazole derivative having the general formula (I).

[0005]

Embedded image

In the above formula, R ¹ is the same or different and is a C ₆ -C ₁₄ aryl group which may have 1 to 3 substituents selected from the following substituent groups or 1 to 3 A 5- or 6-membered aromatic heterocyclic group having 1 or 2 hetero atoms, which may be the same or different from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which may have a substituent; Wherein the group of substituents is halogen; C ₁ -C ₆ alkyl;
C substituted by halogen or C ₁ -C ₆ alkoxy
C ₁ -C ₆ alkyl; C ₁ -C ₆ alkoxy; C ₆ -C ₁₄ aryl, C ₇ -C ₁₈ which may be the same or different and have 1 to 3 substituents selected from the following groups: Aralkyl, C ₆ -C ₁₄ aryloxy or C ₇ -C ₁₈ aralkyloxy (the group of substituents is halogen, C ₁ -C ₆
Alkyl or C ₁ -C ₆ alkoxy. Cyano; nitro; hydroxyl; C ₁ -C ₇ alkanoyl; C _1-)
C ₇ -alkanoyloxy; C ₂ -C ₇ alkoxycarbonyl; amino; carbamoyl; mono (C ₁ -C ₆ alkyl) carbamoyl; di (C ₁ -C ₆ alkyl) carbamoyl and the same or different from the following group Mono-C ₇ -C ₁₅ arylcarbonylamino optionally having 1 to 3 substituents (the group of substituents is halogen, C _1-
C ₆ alkyl or C ₁ -C ₆ alkoxy. ). And R ² are a hydrogen atom; a halogen atom; C ₁ -C ₆
Alkyl group; C ₁ -C ₆ alkyl group substituted by halogen or C ₁ -C ₆ alkoxy; C ₂ -C ₆ alkenyl; C ₂ -C ₆ alkynyl; C ₃ -C ₁₀ cycloalkyl group; C ₃ -C ₁₀ cycloalkenyl group; C ₁ -C ₆ alkoxy group; a cyano group; a carboxyl group; C ₁ -C ₇ alkanoyl group; C ₂ -C ₇ alkoxycarbonyl group; a carbamoyl group; a mono (C ₁ -C ₆ alkyl) A carbamoyl group or a di (C ₁ -C ₆ alkyl) carbamoyl group, wherein R ³ is an amino group, a mono C ₁ -C ₆ alkylamino group, a di (C ₁ -C ₆ alkyl) amino group, a mono C _1- C
₇ alkanoylamino group, mono C ₂ -C ₇ alkoxycarbonylamino group, mono C _7- which may be the same or different and has 1 to 3 substituents selected from the following groups
A C ₁₅ arylcarbonylamino group (a group of the substituents is
Halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy. Or a 5- or 6-membered saturated heterocyclic group containing one nitrogen atom and which may further contain one nitrogen atom or oxygen atom, provided that the group is bonded on the nitrogen atom.
X represents an oxygen atom or a sulfur atom, and n represents 2
And integers from 6 to 6.

In the general formula (I), the “halogen atom” in the definition of the substituent contained in R ¹ and R ² can be, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Is a fluorine atom or a chlorine atom, more preferably a chlorine atom.

In the above description, "C ₁ -C ₆ alkyl group" in the definition of substituents and the like included in R ¹ and R ^{2 and the} like include, for example, methyl, ethyl, propyl, isopropyl, butyl and the like. , Isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2
-Methylpentyl group, 1-methylpentyl group, 3,3-
Dimethylbutyl group, 2,2-dimethylbutyl group, 1,1
-Dimethylbutyl group, 1,2-dimethylbutyl group, 1,
It may be a linear or branched alkyl group having 1 to 6 carbon atoms such as a 3-dimethylbutyl group, a 2,3-dimethylbutyl group or a 2-ethylbutyl group, and the substituent contained in R ¹ is preferably Is a C ₁ -C ₄ alkyl group, more preferably a methyl group or an ethyl group, and particularly preferably a methyl group. R ² is preferably a C ₁ -C ₄ alkyl group, more preferably an ethyl group, a propyl group, an isopropyl group, an isobutyl group or a t-butyl group, and particularly preferably an isopropyl group.

[0009] The above At a, in the definition of R ² 'C ₂ -
“C ₆ alkenyl group” includes, for example, vinyl group, 1-propenyl group, allyl group, 1-methyl-1-propenyl group, 1
-Methyl-2-propenyl group, 2-methyl-1-propenyl group, isopropenyl group, allenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 2-pentenyl group, isoprenyl group, 5-hexenyl Or a linear or branched alkenyl group having 2 to 6 carbon atoms having 1 to 2 double bonds such as a group or 1,4-hexadienyl group, preferably a vinyl group, a 1-propenyl group, Allyl group,
1-methyl-1-propenyl group, isopropenyl group, 2
-Butenyl group or 3-butenyl group, more preferably allyl group, isopropenyl group or 2-butenyl group, particularly preferably allyl group.

[0010] The above-mentioned At a, in the definition of R ² "C ₂ -
“C ₆ alkynyl group” includes, for example, ethynyl group, 1-propynyl group, propargyl group, 1-methyl-2-propynyl group, 2-methyl-2-propynyl group, 2-ethyl-2
-Propynyl group, 2-butynyl group, 1-methyl-2-butynyl group, 2-methyl-2-butynyl group, 3-butynyl group, 2-pentynyl group, 5-hexynyl group or 2-methyl-4-pentynyl group And preferably a straight-chain or branched-chain alkynyl group having 2 to 6 carbon atoms, such as an ethynyl group, a propargyl group, a 2-butynyl group or a 3-butynyl group, and more preferably a propargyl group. is there.

[0011] The above At a "C ₃ in the definition of R ² -
The “C ₁₀ cycloalkyl group” is, for example, an optionally condensed 3- to 10-membered saturated cyclic hydrocarbon such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a norbornyl group or an adamantyl group. And preferably a cyclopropyl, cyclopentyl or cyclohexyl group, more preferably a cyclopropyl group.

[0012] The above At a "C ₃ in the definition of R ² -
“C ₁₀ cycloalkenyl group” is, for example, a 2-cyclopropenyl group, a 2-cyclobutenyl group, a 1-cyclopentenyl group, a 2-cyclopentenyl group, a 3-cyclopentenyl group, a 1-cyclohexenyl group, a 2-cyclohexenyl group A 3- to 10-membered unsaturated cyclic carbon atom having one double bond and optionally being condensed, such as a 3-cyclohexenyl group, a 2-cycloheptenyl group, a 3-norborenyl group or a 3-adamantenyl group; It may be a hydrogen group, preferably a 2-cyclopentenyl group, a 3-cyclopentenyl group, a 2-cyclohexenyl group or a 3-cyclohexenyl group, and more preferably a 2-cyclopentenyl group. The At a, C ₁ substituted with "halogen or C ₁ -C ₆ alkoxy in the definition of substituents and R ² contained in R ¹
-C ₆ alkyl group ", the" halogen atom "of 1 to 5 is the" C ₁ -C ₆ alkyl group "in the attached group or hereinafter" C ₁ -C ₆ alkoxy "is the C ₁ -C ₆ A group bonded to an alkyl group, wherein the group in which halogen is bonded to a C ₁ -C ₆ alkyl group includes, for example, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group,
Fluoroethyl group, 2-chloroethyl group, 2,2,2-
Trifluoroethyl group, 3-fluoropropyl group, 3-
Chloropropyl group, 3-bromopropyl group which may be 4-fluoro-butyl or 6-iodo-hexyl group, C ₁ -
Examples of the group in which C ₆ alkoxy is bonded to a C ₁ -C ₆ alkyl group include a methoxymethyl group, an ethoxymethyl group, a propoxymethyl group, a butoxymethyl group, a methoxyethyl group, an ethoxyethyl group, a propoxyethyl group, and a butoxyethyl group. Group, propoxypropyl group, butoxybutyl group or hexyloxyhexyl group, and the substituent included in R ¹ is preferably 1 to 3 halogen or 1
C ₁ -C ₆ alkyl groups substituted with C ₁ -C ₄ alkoxy, more preferably a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 2-chloroethyl group, A 2,2,2-trifluoroethyl group, a methoxymethyl group or a methoxyethyl group, more preferably a trifluoromethyl group,
It is a 2,2-trifluoroethyl group or a methoxymethyl group, particularly preferably a trifluoromethyl group. or,
R ² is preferably a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group,
-Chloroethyl group, 2-chloroethyl group, 2,2,2-
A trifluoroethyl group, a methoxymethyl group or a methoxyethyl group, more preferably a trifluoromethyl group, a 2-fluoroethyl group, a 1-chloroethyl group or
-Chloroethyl group, particularly preferably a 1-chloroethyl group.

In the above, R ¹ and the like contained in R ¹
"C ₁ -C ₁ " in the definition of the substituent contained in R ² and R ²
" ₆ alkoxy group" refers to a group in which the "C ₁ -C ₆ alkyl group" is bonded to an oxygen atom, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and s-butoxy. Group, t-butoxy group, pentoxy group, isopentoxy group, 2-methylbutoxy group, neopentoxy group, 1-ethylpropoxy group,
Hexyloxy group, 4-methylpentoxy group, 3-methylpentoxy group, 2-methylpentoxy group, 1-methylpentoxy group, 3,3-dimethylbutoxy group, 2,2-
Dimethylbutoxy group, 1,1-dimethylbutoxy group,
It may be a 1,2-dimethylbutoxy group, a 1,3-dimethylbutoxy group, a 2,3-dimethylbutoxy group or a 2-ethylbutoxy group, preferably a C ₁ -C ₄ alkoxy group, more preferably It is a methoxy group or an ethoxy group, particularly preferably a methoxy group.

In the above, in the definition of the substituent contained in R ¹ , “a C ₆ -C ₁₄ aryl group which may be the same or different and has 1 to 3 substituents selected from the following groups: (The group of substituents is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy.) ”Has 1 to 3 substituents selected from the same or different from the above substituent groups. Represents an aromatic hydrocarbon group having 6 to 14 carbon atoms which may be, for example, a phenyl group, a fluorophenyl group, a chlorophenyl group, a dichlorophenyl group, a methylphenyl group,
Trimethylphenyl group, methoxyphenyl group, indenyl group, methylindenyl group, naphthyl group, dichloronaphthyl group, phenanthrenyl group, hexylphenanthrenyl group, anthracenyl group, dimethylanthracenyl group or hexyloxyanthracenyl group. And preferably a phenyl group which may have one or two substituent (s) selected from the group consisting of fluorine, chlorine, methyl and methoxy, and more preferably a phenyl group, It is a fluorophenyl group, a 4-chlorophenyl group, a 2,4-dichlorophenyl group, a 4-methylphenyl group or a 4-methoxyphenyl group, and particularly preferably a phenyl group.

In the above, in the definition of the substituent contained in R ¹ , “a C ₇ -C ₁₈ aralkyl group which may have 1 to 3 substituents, which may be the same or different and selected from the following groups, (The group of substituents is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy.) ”Has 1 to 3 substituents selected from the same or different from the above substituent groups. And one or two phenyl groups or one naphthyl group may be a group bonded to the aforementioned “C ₁ -C ₆ alkyl”, for example, a benzyl group, a fluorobenzyl group, a difluorobenzyl group , Trifluorobenzyl group, chlorobenzyl group, dichlorobenzyl group, trichlorobenzyl group, bromobenzyl group, methylbenzyl group, dimethylbenzyl group, trimethylbenzyl group, ethylbenzyl group,
Propylbenzyl group, methoxybenzyl group, dimethoxybenzyl group, ethoxybenzyl group, hexyloxybenzyl group, diphenylmethyl group, naphthylmethyl group, fluoronaphthylmethyl group, difluoronaphthylmethyl group,
Chloronaphthylmethyl group, dichloronaphthylmethyl group,
Methyl naphthylmethyl group, dimethylnaphthylmethyl group,
Ethyl naphthylmethyl group, phenethyl group, fluorophenethyl group, difluorophenethyl group, chlorophenethyl group, dichlorophenethyl group, methylphenethyl group, trimethylphenethyl group, naphthylethyl group, fluoronaphthylethyl group, chloronaphthylethyl group, phenylpropyl group, Fluorophenylpropyl, chlorophenylpropyl, dichlorophenylpropyl, methylphenylpropyl, dimethylphenylpropyl, trimethylphenylpropyl, naphthylpropyl, iodonaphthylpropyl, hexylnaphthylpropyl, methoxynaphthylpropyl, hexyloxynaphthyl Propyl, phenylbutyl, fluorophenylbutyl, difluorophenylbutyl, chlorophenylbutyl, dichlorophenyl Nirubuchiru group which may be trimethylphenyl butyl group or naphthylbutyl group, preferably a halogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ from the group consisting of alkoxy same or different 1 to 3 is selected A benzyl group or a phenethyl group which may have a substituent, more preferably 1 selected from the group consisting of fluorine, chlorine, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy;
Benzyl group which may have one or more substituents, more preferably benzyl group, fluorobenzyl group, chlorobenzyl group, difluorobenzyl group, dichlorobenzyl group, methylbenzyl group, dimethylbenzyl group or methoxybenzyl. And particularly preferably a benzyl group.

In the above, in the definition of the substituent contained in R ¹ , “the same or different C ₆ -C ₁₄ aryloxy optionally having 1 to 3 substituents selected from the following groups: The group (the group of the substituents is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy) ”is the same as the above“ 1 to 3 selected from the same or different from the following groups.
C ₆ -C ₁₄ aryl groups optionally having one or more substituents (the group of substituents may be halogen, C ₁ -C ₆ alkyl or C ₁ -C ₁₄
C ₆ alkoxy. ) "Represents a group bonded to an oxygen atom, for example, a phenoxy group, a fluorophenoxy group,
Chlorophenoxy group, dichlorophenoxy group, methylphenoxy group, trimethylphenoxy group, methoxyphenoxy group, indenyloxy group, methylindenyloxy group, naphthyloxy group, dichloronaphthyloxy group, phenanthrenyloxy group, hexylphenane It may be a threnyloxy group, an anthracenyloxy group, a dimethylanthracenyloxy group or a hexyloxyanthracenyloxy group, preferably selected from the same or different from the group consisting of fluorine, chlorine, methyl and methoxy. A phenoxy group which may have 1 to 2 substituents, more preferably a phenoxy group, a 4-fluorophenoxy group, a 4-chlorophenoxy group, a 2,4-dichlorophenoxy group,
-Methylphenoxy group or 4-methoxyphenoxy group, particularly preferably phenoxy group.

In the above, in the definition of the substituent contained in R ¹ , “C ₇ -C ₁₈ aralkyloxy which may have 1 to 3 substituents selected from the following groups, which may be the same or different, and The group (the group of the substituents is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy) ”is the same as the above“ 1 to 3 selected from the same or different from the following groups.
C ₇ -C ₁₈ aralkyl groups which may have one or more substituents (groups of such substituents being halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆
—C ₆ alkoxy. ) "Represents a group bonded to an oxygen atom, for example, benzyloxy, fluorobenzyloxy, difluorobenzyloxy, trifluorobenzyloxy, chlorobenzyloxy, dichlorobenzyloxy, trichlorobenzyloxy, bromo Benzyloxy group, methylbenzyloxy group, dimethylbenzyloxy group, trimethylbenzyloxy group, ethylbenzyloxy group, propylbenzyloxy group, methoxybenzyloxy group, dimethoxybenzyloxy group, ethoxybenzyloxy group, hexyloxybenzyloxy group, Diphenylmethoxy group, naphthylmethoxy group, fluoronaphthylmethoxy group, difluoronaphthylmethoxy group, chloronaphthylmethoxy group, dichloronaphthylmethoxy group, methylnaphthylmethoxy group, Methyl naphthyl methoxy group, an ethyl naphthyl methoxy, phenylethoxy group, fluorophenyl ethoxy group, difluorophenyl ethoxy, chlorophenyl ethoxy group,
Dichlorophenylethoxy group, methylphenylethoxy group, trimethylphenylethoxy group, naphthylethoxy group, fluoronaphthylethoxy group, chloronaphthylethoxy group, phenylpropoxy group, fluorophenylpropoxy group, chlorophenylpropoxy group, dichlorophenylpropoxy group, methylphenylpropoxy group, Dimethylphenylpropoxy, trimethylphenylpropoxy, naphthylpropoxy, iodonaphthylpropoxy, hexylnaphthylpropoxy, methoxynaphthylpropoxy, hexyloxynaphthylpropoxy, phenylbutoxy, fluorophenylbutoxy, difluorophenylbutoxy, chlorophenyl Butoxy, dichlorophenylbutoxy, trimethylphenylbutoxy or Be a Nafuchirubutokishi group, preferably a halogen, C ₁ -C ₄ alkyl and C ₁ -C ₄
A benzyloxy group or a phenylethoxy group, which may have 1 to 3 substituents which are the same or different and are selected from the group consisting of alkoxy, more preferably fluorine, chlorine, C ₁ -C ₄ alkyl And a benzyloxy group optionally having one substituent selected from the group consisting of C ₁ -C ₄ alkoxy, and more preferably a benzyloxy group, a 4-fluorobenzyloxy group, Chlorobenzyloxy group, 2,4-difluorobenzyloxy group,
2,4-dichlorobenzyloxy group, 4-methylbenzyloxy group, 2,4-dimethylbenzyloxy group or 4
-Methoxybenzyloxy group, particularly preferably a benzyloxy group.

In the above, the substituent contained in R ¹ and R ¹
“C ₁ -C ₇ alkanoyl group” in the definition of ² represents a hydrogen atom or a group in which the above “C ₁ -C ₆ alkyl” is bonded to a carbonyl group, for example, formyl group, acetyl group, propionyl group, butyryl group , An isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group, a hexanoyl group or a heptanoyl group, preferably a formyl group or an acetyl group, particularly preferably an acetyl group.

In the above, “C ₁ -C ₇ alkanoyloxy group” in the definition of the substituent contained in R ¹ indicates a group in which the above “C ₁ -C ₇ alkanoyl group” is bonded to an oxygen atom, For example, formyloxy group, acetoxy group, propionyloxy group, butyryloxy group, isobutyryloxy group, valeryloxy group, isovaleryloxy group,
It may be a pivaloyloxy group, a hexanoyloxy group or a heptanoyloxy group, preferably a formyloxy group or an acetoxy group, particularly preferably an acetoxy group.

In the above, the substituent contained in R ¹ and R ¹
"C ₂ -C ₇ alkoxycarbonyl group" in the ^two definitions, a group wherein the above "C ₁ -C ₆ alkoxy group" is bonded to a carbonyl group, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group,
Isopropoxycarbonyl group, butoxycarbonyl group,
Isobutoxycarbonyl group, s-butoxycarbonyl group, t-butoxycarbonyl group, pentoxycarbonyl group, isopentoxycarbonyl group, 2-methylbutoxycarbonyl group, neopentoxycarbonyl group, 1-ethylpropoxycarbonyl group, hexyloxy Carbonyl group, 4-methylpentoxycarbonyl group, 3-methylpentoxycarbonyl group, 2-methylpentoxycarbonyl group, 1-methylpentoxycarbonyl group, 3,3-dimethylbutoxycarbonyl group, 2,2-dimethylbutoxy Carbonyl group, 1,1-dimethylbutoxycarbonyl group, 1,2-dimethylbutoxycarbonyl group, 1,3-
It may be a dimethylbutoxycarbonyl group, a 2,3-dimethylbutoxycarbonyl group or a 2-ethylbutoxycarbonyl group, preferably a C ₂ -C ₅ alkoxycarbonyl group, more preferably a methoxycarbonyl group or an ethoxycarbonyl group. And particularly preferably a methoxycarbonyl group.

In the above, “mono C” in the definition of R ³
₁ -C ₆ alkylamino group "refers to a group wherein the above" C ₁ -C ₆ alkyl group "is bonded to an amino group, for example methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, s- butyl amino group, t- butyl amino group which may be pentylamino group or hexylamino group, preferably a mono-C ₁ -C ₄ alkylamino group, more preferably methylamino Or an ethylamino group, particularly preferably a methylamino group.

[0022] At a above, "di (C in the definition of R ³
₁ -C ₆ alkyl) amino group ", for example, N, N- dimethylamino group, N- ethyl -N- methylamino group, N
-Methyl-N-propylamino group, N-isopropyl-
N-methylamino group, N-butyl-N-methylamino group, N-isobutyl-N-methylamino group, Ns-butyl-N-methylamino group, Nt-butyl-N-methylamino group, N, N-diethylamino group, N-ethyl-
N-propylamino group, N-ethyl-N-isobutylamino group, N, N-dipropylamino group, N, N-dibutylamino group, N, N-dipentylamino group or N, N-
It may be a dihexylamino group, preferably di (C ₁ -C ₄
Alkyl) amino group, more preferably N, N-dimethylamino group or N, N-diethylamino group, particularly preferably N, N-dimethylamino group.

[0023] The above At a "C ₁ in the definition of R ³ -
C ₇ alkanoylamino group "refers to a group wherein the above" C ₁ -C ₇ alkanoyl group "is bonded to an amino group, for example,
Formylamino group, acetylamino group, propionylamino group, butyrylamino group, isobutyrylamino group, valerylamino group, isovalerylamino group, pivaloylamino group, hexanoylamino group or heptanoylamino group, preferably formyl It is an amino group or an acetylamino group, particularly preferably an acetylamino group.

[0024] The above At a "C ₂ in the definition of R ³ -
The “C ₇ alkoxycarbonylamino group” is the same as the aforementioned “C _2-
A `` C ₇ alkoxycarbonyl group '' represents a group bonded to an amino group, for example, methoxycarbonylamino group, ethoxycarbonylamino group, propoxycarbonylamino group, isopropoxycarbonylamino group, butoxycarbonylamino group, isobutoxycarbonylamino group, s
-Butoxycarbonylamino group, t-butoxycarbonylamino group, pentoxycarbonylamino group, isopentoxycarbonylamino group, 2-methylbutoxycarbonylamino group, neopentoxycarbonylamino group, 1
-Ethylpropoxycarbonylamino group, hexyloxycarbonylamino group, 4-methylpentoxycarbonylamino group, 3-methylpentoxycarbonylamino group, 2-methylpentoxycarbonylamino group, 1-methylpentoxycarbonylamino group, 3 2,3-dimethylbutoxycarbonylamino group, 2,2-dimethylbutoxycarbonylamino group, 1,1-dimethylbutoxycarbonylamino group, 1,2-dimethylbutoxycarbonylamino group, 1,3-dimethylbutoxycarbonylamino group, 2 , 3-dimethyl-butoxy be a carbonylamino group or a 2-ethyl-butoxycarbonylamino group, preferably a C ₂ -C ₅ alkoxycarbonyl group,
More preferably, it is a methoxycarbonylamino group or an ethoxycarbonylamino group, particularly preferably a methoxycarbonylamino group.

In the above, the substituent contained in R ¹ and R
The “mono (C ₁ -C ₆ alkyl) carbamoyl group” in the definition of ² includes, for example, a methylcarbamoyl group, an ethylcarbamoyl group, a propylcarbamoyl group, an isopropylcarbamoyl group, a butylcarbamoyl group, an isobutylcarbamoyl group, an s-butylcarbamoyl group, t- butylcarbamoyl group which may be pentylcarbamoyl group or hexylcarbamoyl group, preferably a mono (C ₁ -C ₄ alkyl) carbamoyl group, more preferably a methylcarbamoyl group or ethylcarbamoyl group.

In the above, the substituent contained in R ¹ and R
The “di (C ₁ -C ₆ alkyl) carbamoyl group” in the definition of ² is, for example, an N, N-dimethylcarbamoyl group,
N-ethyl-N-methylcarbamoyl group, N, N-diethylcarbamoyl group, N, N-dipropylcarbamoyl group, N, N-diisopropylcarbamoyl group, N, N-
Dibutylcarbamoyl group, N, N-diisobutylcarbamoyl group, N, N-di-s-butylcarbamoyl group,
It may be an N, N-di-t-butylcarbamoyl group, an N, N-dipentylcarbamoyl group or an N, N-dihexylcarbamoyl group, preferably a di (C ₁ -C ₄ alkyl) carbamoyl group, more preferably Is an N, N-dimethylcarbamoyl group or an N, N-diethylcarbamoyl group, particularly preferably an N, N-dimethylcarbamoyl group.

In the above, the substituent contained in R ¹ and R
^In the definition of ³ , "mono-C _7- which may have the same or different and may have 1 to 3 substituent (s) selected from the following groups:
The C ₁₅ arylcarbonylamino group (the group of the substituents is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy) ”is the same as the“ 1 to 4 selected from the same or different from the following groups. C _6- which may have three substituents
A C ₁₄ aryl group (the group of substituents is halogen, C ₁ -C
₆ alkyl or C ₁ -C ₆ alkoxy. ) "Represents a group bonded to a carbonylamino group, for example, benzoylamino, fluorobenzoylamino, chlorobenzoylamino, dichlorobenzoylamino, toluoylamino, trimethylbenzoylamino, anisoylamino, indole Noylamino group, methylindenoylamino group, naphthoylamino group, dichloronaphthoylamino group, phenanthrenoylamino group, hexylphenanthrenoylamino group, anthracenoylamino group, dimethylanthracenoylamino group or hexyl An oxyanthracenoylamino group, preferably a benzoylamino group which may have 1 to 2 substituents which are the same or different and are selected from the group consisting of fluorine, chlorine, methyl and methoxy; More preferably, a benzoylamino group, 4 Fluorobenzoyl group, 4-chlorobenzoyl group, 2,4-dichloro-benzoylamino group, 4-toluoyl-amino group or a 4-anisoyl group, particularly preferably a benzoylamino group.

In the above description, in the definition of R ³ , “a 5- or 6-membered saturated heterocyclic group containing one nitrogen atom and which may further contain one nitrogen atom or oxygen atom, Is bonded on a nitrogen atom.) "Can be, for example, a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, a piperidyl group, a piperazinyl group or a morpholinyl group, and is preferably a piperidyl group or a morpholinyl group.

In the definition of R ¹ , “a C ₆ -C ₁₄ aryl group which may be the same or different and has 1 to 3 substituents selected from the following substituent groups” includes, for example, May be a phenyl group, an indenyl group, a naphthyl group, a phenanthrenyl group or an anthracenyl group, which may be substituted by the substituent, and preferably 1 to 3 identical or different ones selected from the following substituent groups. It may have a substituent is a good C ₆ -C ₁₄ aryl group [the group of the substituents are halogen; C ₁ -C ₆ alkyl; C ₁ -C substituted by halogen or C ₁ -C ₆ alkoxy ₆ alkyl; C ₁ -C ₆ alkoxy; C ₆ -C ₁₄ aryl which may be the same or different and have 1 to 3 substituents selected from the following groups (the group of substituents is halogen, C
It is ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy. ); Benzyl, fluorobenzyl, chlorobenzyl, difluorobenzyl, dichlorobenzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl; phenoxy, 4-fluorophenoxy, 4-chlorophenoxy, 2,4-dichlorophenoxy, 4-methylphenoxy, -Methoxyphenoxy; benzyloxy, 4-fluorobenzyloxy, 4-chlorobenzyloxy,
2,4-difluorobenzyloxy, 2,4-dichlorobenzyloxy, 4-methylbenzyloxy, 2,4-
Dimethylbenzyloxy, 4-methoxybenzyloxy; cyano; nitro; hydroxyl; acetoxy; C ₂ -C ₇
Alkoxy; amino; carbamoyl; mono (C ₁ -C ₆ alkyl) carbamoyl; di (C ₁ -C ₆₎
Alkyl) carbamoyl; benzoylamino, 4-fluorobenzoylamino, 4-chlorobenzoylamino,
2,4-dichlorobenzoylamino, 4-toluoylamino and 4-anisoylamino. And more preferably a C ₆ -C ₁₄ aryl group which may have 1 to 3 substituents, which are the same or different and are selected from the following substituent groups. ; C ₁ -C ₆ alkyl; halogen or C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl substituted by; C ₁ -C ₆ alkoxy; same or different 1 to 3 of which are selected from the following group C ₆ -C ₁₄ aryl which may have a substituent (the group of the substituents is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy); cyano; C ₂ -C ₇ alkoxy Carbonyl; carbamoyl; mono (C ₁ -C ₆ alkyl) carbamoyl; and di (C ₁ -C ₆ alkyl) carbamoyl. ], Even more preferably the same or different and are 1 to 3 of which may have a substituent C ₆ -C ₁₄ aryl group selected from the following substituent group [the group of the substituents are halogen , C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, methoxymethyl, methoxyethyl, C ₁ -C ₄ alkoxy, phenyl, 4- Fluorophenyl, 4-chlorophenyl, 2,
4-dichlorophenyl, 4-methylphenyl, 4-methoxyphenyl, cyano, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl, N, N-dimethylcarbamoyl and N, N-diethylcarbamoyl. And more preferably a phenyl group which may have 1 to 3 substituents which are the same or different and are selected from the following substituent groups [the substituent groups are halogen, methyl, ethyl , Trifluoromethyl, methoxy, phenyl, cyano, methoxycarbonyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl and N, N-dimethylcarbamoyl. And even more preferably a phenyl group which may have the same or different and one or two substituents selected from the following substituent groups [the substituent group is fluorine, chlorine, Methyl, ethyl, trifluoromethyl and methoxy. And particularly preferably a phenyl group, a fluorophenyl group, a chlorophenyl group, a difluorophenyl group, a dichlorophenyl group or a methylphenyl group, and most preferably a phenyl group, a 2-chlorophenyl group, a 4-chlorophenyl group, 4-difluorophenyl group or 2,
4-Dichlorophenyl group. The number of substituents on the aryl group is preferably 1 to 3, and more preferably 1
To 2, particularly preferably 2.

In the above, the definition of R ^{1 is} the same as or different from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom which may have 1 to 3 said substituents. The "5- or 6-membered aromatic heterocyclic group having two heteroatoms" is, for example, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, which may be substituted by the substituent.
Furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl,
A nitrogen atom, an oxygen atom and a sulfur atom which may be a pyrazinyl group, a pyrimidinyl group or a pyridazinyl group, and which may have the same or different and may have 1 to 3 substituents selected from the following substituent groups. A 5- or 6-membered aromatic heterocyclic group having 1 or 2 heteroatoms, which is the same or different from the group consisting of the following: [The substituent group is halogen; C ₁ -C ₆ alkyl; Halogen or C _1-
C ₁ -C ₆ alkyl substituted with C ₆ alkoxy; C ₁
-C ₆ alkoxy; C ₆ -C ₁₄ which may have the same or different and may have 1 to 3 substituent (s) selected from the following groups:
Aryl (the group of substituents is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy); benzyl, fluorobenzyl, chlorobenzyl, difluorobenzyl, dichlorobenzyl, methylbenzyl, dimethylbenzyl, methoxy Benzyl; phenoxy, 4-fluorophenoxy, 4-chlorophenoxy, 2,4-dichlorophenoxy, 4-methylphenoxy, 4-methoxyphenoxy; benzyloxy, 4-fluorobenzyloxy, 4-chlorobenzyloxy, 2,4- Difluorobenzyloxy, 2,4-dichlorobenzyloxy, 4-
Methylbenzyloxy, 2,4-dimethyl-benzyloxy, 4-methoxybenzyloxy; cyano; nitro; hydroxyl; acetoxy; C ₂ -C ₇ alkoxycarbonyl;
Amino; carbamoyl; mono (C ₁ -C ₆ alkyl) carbamoyl; di (C ₁ -C ₆ alkyl) carbamoyl;
Benzoylamino, 4-fluorobenzoylamino, 4
-Chlorobenzoylamino, 2,4-dichlorobenzoylamino, 4-toluoylamino and 4-anisoylamino. And more preferably the same or different from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which may have 1 to 3 substituents which are the same or different and which are selected from the following substituent groups. A 5- or 6-membered aromatic heterocyclic group having 1 or 2 heteroatoms, wherein said group of substituents is halogen; C ₁ -C ₆ alkyl; halogen or C ₁ -C ₆ alkoxy. Substituted C ₁ -C ₆ alkyl; C ₁ -C ₆ alkoxy; C ₆ -C ₁₄ aryl which may be the same or different and has 1 to 3 substituents selected from the following group (the substituted The group of groups is halogen,
C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy. ); Cyano; C ₂ -C ₇ alkoxycarbonyl; carbamoyl; mono (C ₁ -C ₆ alkyl) carbamoyl; and di (C ₁ -C ₆ alkyl) carbamoyl. And more preferably the same or different from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which may have one or two substituents which are the same or different and are selected from the following substituent groups. 5 having one or two heteroatoms
And 6-membered aromatic heterocyclic groups. [The group of the substituents is halogen, C ₁ -C ₄ alkyl, fluoromethyl,
Difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, methoxymethyl, methoxyethyl, C ₁ -C ₄ alkoxy, phenyl, 4-fluorophenyl, 4-chlorophenyl, 2,
4-dichlorophenyl, 4-methylphenyl, 4-methoxyphenyl, cyano, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl, N, N-dimethylcarbamoyl and N, N-diethylcarbamoyl. And more preferably a furyl group, a thienyl group or a pyridyl group, which may have one or two substituents, which may be the same or different and are selected from the following substituent groups [the group of the substituents: Is halogen, methyl, ethyl, trifluoromethyl, methoxy,
Phenyl, cyano, methoxycarbonyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl and N,
N-dimethylcarbamoyl. And even more preferably a furyl group, a thienyl group or a pyridyl group, which may have one substituent selected from the following substituent group [the substituent group is fluorine, chlorine , Methyl, ethyl,
Trifluoromethyl and methoxy. ], Particularly preferably a 2-furyl group, a 3-furyl group, a 2-thienyl group or a 3-thienyl group, and most preferably a 2-furyl group or a 2-thienyl group. The number of substituents on the aromatic heterocyclic group is preferably 1 to 3, more preferably 1 or 2, and particularly preferably 1. In addition, the bond between the aromatic heterocyclic group and the isoxazole ring is preferably a bond via a carbon atom on the aromatic heterocyclic ring.

In the above, X is preferably an oxygen atom.

In the above, n is preferably an integer of 2 to 4, particularly preferably 2.

The compound (I) of the present invention can be converted into an acid addition salt according to a conventional method. For example, compound (I) is reacted with a corresponding acid in a solvent (for example, ethers, esters or alcohols, particularly ethers) for 5 minutes to 3 minutes at room temperature.
It can be obtained by treating for 0 minutes and collecting the precipitated crystals by filtration or distilling off the solvent under reduced pressure. Such salts include, for example, mineral salts such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate or phosphate; methanesulfonic acid Salts, sulphonates such as trifluoromethanesulphonate, ethanesulphonate, benzenesulphonate or p-toluenesulphonate; fumarate, succinate, citrate, tartrate, oxalate Or a carboxylate such as maleate; or an amino acid salt such as glutamate or aspartate, preferably a mineral acid salt (especially hydrochloride).

The compound (I) of the present invention may have an asymmetric carbon in the molecule, and each may have an R-coordinate or S-coordinate stereoisomer. Alternatively, any mixture thereof in any ratio is included in the present invention.

Compound (I) of the present invention or a salt thereof is
By leaving in the air or recrystallizing,
In some cases, the compound absorbs water and becomes adsorbed water or forms a hydrate, and a compound salt containing such water is also included in the present invention.

In the compound having the general formula (I),
Preferably, (1) R ¹ is the same or different and is a C ₆ -C ₁₄ aryl group which may have 1 to 3 substituents selected from the following substituent groups, or 1 to 3 A 5- or 6-membered aromatic heterocyclic group having 1 or 2 hetero atoms, which may be the same as or different from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which may have a substituent; A compound [the group of the substituents is halogen; C ₁ -C ₆ alkyl;
C substituted by halogen or C ₁ -C ₆ alkoxy
C ₁ -C ₆ alkyl; C ₁ -C ₆ alkoxy; C ₆ -C ₁₄ aryl which may be the same or different and have 1 to 3 substituents selected from the following group (the group of substituents is , Halogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy)); benzyl, fluorobenzyl, chlorobenzyl, difluorobenzyl, dichlorobenzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl; phenoxy, 4-fluorophenoxy , 4-chlorophenoxy, 2,4-dichlorophenoxy, 4-methylphenoxy, 4-methoxyphenoxy; benzyloxy, 4-fluorobenzyloxy, 4-chlorobenzyloxy,
2,4-difluorobenzyloxy, 2,4-dichlorobenzyloxy, 4-methylbenzyloxy, 2,4-
Dimethylbenzyloxy, 4-methoxybenzyloxy; cyano; nitro; hydroxyl; acetoxy; C ₂ -C ₇
Alkoxy; amino; carbamoyl; mono (C ₁ -C ₆ alkyl) carbamoyl; di (C ₁ -C ₆₎
Alkyl) carbamoyl; benzoylamino, 4-fluorobenzoylamino, 4-chlorobenzoylamino,
2,4-dichlorobenzoylamino, 4-toluoylamino and 4-anisoylamino. ], (2) R
¹ is the same or different and is 1 selected from the following substituent group
A C ₆ -C ₁₄ aryl group optionally having 1 to 3 substituents or a nitrogen atom optionally having 1 to 3 substituents,
5 to 6 members having 1 or 2 heteroatoms selected from the group consisting of oxygen and sulfur atoms, which are the same or different
A compound which is a membered aromatic heterocyclic group [the group of substituents is
Halogen; C ₁ -C ₆ alkyl; halogen or C ₁
C ₁ -C ₆ alkyl substituted with —C ₆ alkoxy; C
₁ -C ₆ alkoxy; same or different groups of 1 to 3 of which may have a substituent C ₆ -C ₁₄ aryl (the substituent is selected from the following group are halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy.); Cyano; C ₂ -C ₇ alkoxycarbonyl; carbamoyl;
Mono (C ₁ -C ₆ alkyl) carbamoyl; and di (C
It is ₁ -C ₆ alkyl) carbamoyl. ], (3)
R ¹ is a C ₆ -C ₁₄ aryl group which may be the same or different and has 1 to 3 substituents selected from the following substituent groups, or has 1 to 2 substituents; A compound which is a 5- or 6-membered aromatic heterocyclic group having 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom or different from each other [the substituent of the substituent The group is halogen, C ₁ -C ₄ alkyl, fluoromethyl,
Difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, methoxymethyl, methoxyethyl, C ₁ -C ₄ alkoxy, phenyl, 4-fluorophenyl, 4-chlorophenyl, 2,
4-dichlorophenyl, 4-methylphenyl, 4-methoxyphenyl, cyano, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl, N, N-dimethylcarbamoyl and N, N-diethylcarbamoyl. ], (4) R
¹ is the same or different and is 1 selected from the following substituent group
A compound which is a furyl group, a thienyl group or a pyridyl group which may have 1 to 2 phenyl groups or 1 to 2 substituents which may have 1 to 3 substituents; Halogen, methyl, ethyl, trifluoromethyl, methoxy, phenyl, cyano, methoxycarbonyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl and N, N-dimethylcarbamoyl. ], (5) R
¹ is a phenyl group which may have 1 or 2 substituent (s) which are the same or different and which is selected from the following substituent groups, or a furyl group, thienyl group or pyridyl which may have 1 substituent. A group of compounds [a group of such substituents is fluorine, chlorine, methyl, ethyl, trifluoromethyl and methoxy]. And (6) R ¹ is phenyl, fluorophenyl, chlorophenyl, difluorophenyl, dichlorophenyl, methylphenyl, 2-furyl, 3
- a furyl group, a compound is 2-thienyl or 3-thienyl group, (7) R ¹ is a phenyl group, a 2-chlorophenyl group, 4-chlorophenyl group, 2,4-difluorophenyl group, 2,4-dichlorophenyl (8) R ² is a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, -Fluoroethyl group, 1-chloroethyl group, 2-
Chloroethyl group, 2,2,2-trifluoroethyl group,
Methoxymethyl group, methoxyethyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, 2-cyclopentenyl group, 3-cyclopentenyl group, 2-cyclohexenyl Group, 3-cyclohexenyl group, methoxy group, ethoxy group, cyano group, carboxy group, formyl group, acetyl group, methoxycarbonyl group, ethoxycarbonyl group, carbamoyl group, methylcarbamoyl group, ethylcarbamoyl group or N, N-dimethyl A compound which is a carbamoyl group, (9) R ² is a hydrogen atom, a halogen atom,
C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkenyl group or C
A compound which is a _2- C ₆ alkynyl group, (10) R ²
But a hydrogen atom, a halogen atom, C ₁ -C ₄ alkyl group,
(11) a compound wherein R ² is a hydrogen atom, a chlorine atom, an ethyl group, a propyl group, an isopropyl group, an isobutyl group or a t-butyl group; , (1
2) a compound wherein R ² is a hydrogen atom or an isopropyl group; (13) R ³ is an amino group, a mono C ₁ -C ₆ alkylamino group, a di (C ₁ -C ₆ alkyl) amino group or one And a 5- or 6-membered saturated heterocyclic group which may further contain one nitrogen atom or oxygen atom (however,
The group is attached on the nitrogen atom. ), (1)
4) a compound wherein R ³ is an amino group, a methylamino group, an ethylamino group, an N, N-dimethylamino group, a piperidyl group or a morpholinyl group; (15) a compound wherein R ³ is an amino group; Compounds in which X is an oxygen atom, (17) a compound in which n is 2 are mentioned. For R ¹ , the preferred order increases from (1) to (7).
With respect to ² up is preferred ranking in the order of (12) to (8), with respect to R ³ amounting is suitable ranking in the order of from (13) (15).

The compounds having the general formula (I) include (1)-(7), (8)-(12), (13)
-It is possible to select 2 to 5 from the group consisting of (15), (16) and (17) and to arbitrarily combine them. Examples of suitable compounds in the combination include ( 18) R ¹ is a C ₆ -C ₁₄ aryl group which is the same or different and may have 1 to 3 substituents selected from the following substituent groups, or has 1 to 3 said substituents. A 5- or 6-membered aromatic heterocyclic group having 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom which may be the same or different [substituent group, halogen; are the same or different and selected from the following group: C ₁ -C ₆ alkyl; halogen or C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl substituted; C ₁ -C ₆ alkoxy 1 may have a three substituents C ₆ -C ₁₄ Reel (group of the substituents,
Halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy. ); Cyano; C ₂ -C ₇ alkoxycarbonyl; carbamoyl; mono (C ₁ -C ₆ alkyl) carbamoyl; and di (C ₁ -C ₆ alkyl) carbamoyl. And R ² is a hydrogen atom, a halogen atom, C ₁
-C ₆ alkyl group, C ₂ -C ₆ alkenyl group or C _2-
A C ₆ alkynyl group, wherein R ³ is an amino group, a mono C ₁
A —C ₆ alkylamino group, a di (C ₁ -C ₆ alkyl) amino group or a 5- to 6-membered saturated heterocyclic ring containing one nitrogen atom and which may further contain one nitrogen atom or oxygen atom A compound which is a group (however, the group is bonded on a nitrogen atom); (19) a compound in which R ¹ is the same or different and has 1 to 3 substituents selected from the following substituent group; Good C ₆
-C ₁₄ may have an aryl group or 1 to 3 of said substituents, with the nitrogen atom, 1 or 2 heteroatoms selected same or different from the group consisting of an oxygen atom and a sulfur atom a 5-membered or 6-membered aromatic heterocyclic group [the group of substituents are halogen; C ₁ -C ₆ alkyl; halogen or C ₁ -C C ₁ -C ₆ substituted with ₆ alkoxy alkyl; C ₁ -C ₆ alkoxy; same or different may have 1 to 3 substituents selected from the following group C
₆ -C ₁₄ aryl (the group of the substituents are halogen, C ₁
—C ₆ alkyl or C ₁ -C ₆ alkoxy. ); Cyano; C ₂ -C ₇ alkoxycarbonyl; carbamoyl; mono (C ₁ -C ₆ alkyl) carbamoyl; and di (C ₁ -C ₆ alkyl) carbamoyl. And R ² is a hydrogen atom, a halogen atom, C ₁ -C ₆
A compound wherein R ³ is an amino group, X is an oxygen atom, and n is 2, (20) R ¹ is an alkyl group, a C ₂ -C ₆ alkenyl group or a C ₂ -C ₆ alkynyl group; ,
1 to 3 identical or different selected from the following substituent groups
C ₆ -C ₁₄ aryl group or 1
A 5- or 6-membered aromatic having 1-2 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which may have 1 to 2 substituents, A heterocyclic group [the group of the substituents is halogen, C
₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,
2,2-trifluoroethyl, methoxymethyl, methoxyethyl, C ₁ -C ₄ alkoxy, phenyl, 4-fluorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 4-methylphenyl, 4-methoxyphenyl, cyano, Methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl, N, N-dimethylcarbamoyl and N, N-diethylcarbamoyl. A compound wherein R ² is a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, an allyl group, an isopropenyl group, a 2-butenyl group or a propargyl group, and R ³ is an amino group; A compound wherein n is 2 and (21) R ¹ is the same or different and has a phenyl group or 1 to 2 which may have 1 to 3 substituents selected from the following substituent groups; A furyl group, a thienyl group or a pyridyl group, which may have one or more of the substituents [a group of the substituents is halogen, methyl, ethyl, trifluoromethyl, methoxy, phenyl, cyano, methoxycarbonyl, carbamoyl , Methylcarbamoyl, ethylcarbamoyl and N, N-dimethylcarbamoyl. ], R ² is a hydrogen atom, a halogen atom, C ₁ -C ₄ alkyl group, allyl group, isopropenyl group, 2-butenyl or propargyl group, R ³
Is an amino group, X is an oxygen atom, and n is 2. (22) R ¹ has 1 or 2 substituents, which are the same or different and are selected from the following substituent groups. A phenyl group or a furyl group, a thienyl group or a pyridyl group which may have one such substituent [the group of such substituents is fluorine, chlorine, methyl, ethyl, trifluoromethyl and methoxy; is there. R ² is a hydrogen atom, a chlorine atom, an ethyl group, a propyl group, an isopropyl group, an isobutyl group or a t-butyl group, R ³ is an amino group, X is an oxygen atom, and n is 2 (2)
3) R ¹ is a fluorophenyl group, a chlorophenyl group, a difluorophenyl group, a dichlorophenyl group, a methylphenyl group, a 2-furyl group, a 3-furyl group, a 2-thienyl group or a 3-thienyl group, and R ² is Hydrogen atom,
A compound wherein a chlorine atom, an ethyl group, a propyl group, an isopropyl group, an isobutyl group or a t-butyl group, R ³ is an amino group, X is an oxygen atom, and n is 2;
(24) R ¹ is a phenyl group, 2-chlorophenyl group, 4-chlorophenyl group, 2,4-difluorophenyl group, 2,4-dichlorophenyl group, 2-furyl group or 2-thienyl group, and R ² is , A hydrogen atom or an isopropyl group, R ³ is an amino group, X is an oxygen atom, and n is 2. As for the above, in the order of (18) to (24) The preferred rank goes up.

The representative compounds of the present invention include, for example, the compounds described in the following table, but the present invention is not limited to these compounds. The abbreviations in the table are as follows. Ac: Acetyl All: Allyl Bn: Benzyl Bu: Butyl Bu ^i: isobutyl Bu ^s: secondary butyl Bu ^t: data - tert-butyl Bun (2): 2- butenyl Bz: Benzoyl Et: Ethyl Fur (2): 2- furyl Hex: Hexyl Imid (2): 2-imidazolyl Inde (1): 1-indenyl Isothiz (3): 3-isothiazolyl Isox (3): 3-isoxazolyl Me: Methyl Moc: methoxycarbonyl Mor (4): 4-mol Np (1): 1- naphthyl Np (2): 2- naphthyl Oxa (2): 2- oxazolyl Pen ^c (2): 2- cyclopentenyl Ph: phenyl Pip (1): 1- piperidyl Piz (1): 1-piperazinyl Pn: Chill Pn ^c: Cyclopentyl Pn ^i: isopentyl Pr: propyl Pr ^c: cyclopropyl Pr ^i: isopropyl Pre ^i: isopropenyl Prg: propargyl Pym (2): 2- pyrimidinyl Pyr (2): 2- pyridyl Pyr (3): 3-pyridyl Pyr (4): 4-pyridyl Pyrd (1): 1-pyrrolidinyl Pyrr (3): 3-pyrrolyl Pyz (2): 2-pyrazinyl Pyza (1): 1-pyrazolyl Pyzn (3): 3- Pyridazinyl Thi (2): 2-thienyl Thi (3): 3-thienyl Thiz (2): 2-thiazolyl

[0039]

Embedded image

[0040]

[Table 1] Compound number R ¹ R ^Two R ^Three X n 1 Ph H NH _Two O 2 2 Ph H NH _Two O 3 3 Ph H NH _Two O 4 4 Ph F NH _Two O 2 5 Ph Cl NH _Two O 2 6 Ph Me NH _Two O 2 7 Ph Et NH _Two O 2 8 Ph Pr NH _Two O 2 9 Ph Pr ⁱ NH _Two O 2 10 Ph Bu NH _Two O 2 11 Ph Bu ⁱ NH _Two O 2 12 Ph Bu ^s NH _Two O 2 13 Ph Bu ^t NH _Two O 2 14 Ph CF _Three NH _Two O 2 15 Ph H NH _Two S 2 16 Ph H NH _Two S 3 17 Ph H NH _Two S 4 18 Ph F NH _Two S 2 19 Ph Cl NH _Two S 2 20 Ph Me NH _Two S 2 21 Ph Et NH _Two S 2 22 Ph Pr NH _Two S 2 23 Ph Pr ⁱ NH _Two S 2 24 Ph Bu NH _Two S 2 25 Ph H NHMe O 2 26 Ph H NHEt O 2 27 Ph HN (Me) _Two O 2 28 Ph H Pip (1) O 2 29 Ph H Mor (4) O 2 30 2-F-Ph H NH _Two O 2 31 2-F-Ph F NH _Two O 2 32 2-F-Ph Cl NH _Two O 2 33 2-F-Ph Me NH _Two O 2 34 2-F-Ph Et NH _Two O 2 35 2-F-Ph Pr NH _Two O 2 36 2-F-Ph Pr ⁱ NH _Two O 2 37 2-F-Ph Bu NH _Two O 2 38 2-F-Ph Bu ⁱ NH _Two O 2 39 2-F-Ph Bu ^s NH _Two O 2 40 2-F-Ph Bu ^t NH _Two O 2 41 2-F-Ph H NH _Two S 2 42 2-F-Ph F NH _Two S 2 43 2-F-Ph Cl NH _Two S 2 44 2-F-Ph Me NH _Two S 2 45 2-F-Ph Et NH _Two S 2 46 2-F-Ph Pr NH _Two S 2 47 2-F-Ph Pr ⁱ NH _Two S 2 48 3-F-Ph H NH _Two O 2 49 3-F-Ph F NH _Two O 2 50 3-F-Ph Cl NH _Two O 2 51 3-F-Ph Me NH _Two O 2 52 3-F-Ph Et NH _Two O 2 53 3-F-Ph Pr NH _Two O 2 54 3-F-Ph Pr ⁱ NH _Two O 2 55 3-F-Ph Bu NH _Two O 2 56 3-F-Ph Bu ⁱ NH _Two O 2 57 3-F-Ph Bu ^s NH _Two O 2 58 3-F-Ph Bu ^t NH _Two O 2 59 3-F-Ph H NH _Two S 2 60 3-F-Ph F NH _Two S 2 61 3-F-Ph Cl NH _Two S 2 62 3-F-Ph Me NH _Two S 2 63 3-F-Ph Et NH _Two S 2 64 3-F-Ph Pr NH _Two S 2 65 3-F-Ph Pr ⁱ NH _Two S 2 66 4-F-Ph H NH _Two O 2 67 4-F-Ph H NH _Two O 3 68 4-F-Ph H NH _Two O 4 69 4-F-Ph F NH _Two O 2 70 4-F-Ph Cl NH _Two O 2 71 4-F-Ph Me NH _Two O 2 72 4-F-Ph Et NH _Two O 2 73 4-F-Ph Pr NH _Two O 2 74 4-F-Ph Pr ⁱ NH _Two O 2 75 4-F-Ph Bu NH _Two O 2 76 4-F-Ph Bu ⁱ NH _Two O 2 77 4-F-Ph Bu ^s NH _Two O 2 78 4-F-Ph Bu ^t NH _Two O 2 79 4-F-Ph H NH _Two S 2 80 4-F-Ph H NH _Two S 3 81 4-F-Ph H NH _Two S 4 82 4-F-Ph F NH _Two S 2 83 4-F-Ph Cl NH _Two S 2 84 4-F-Ph Me NH _Two S 2 85 4-F-Ph Et NH _Two S 2 86 4-F-Ph Pr NH _Two S 2 87 4-F-Ph Pr ⁱ NH _Two S 2 88 4-F-Ph H NHMe O 2 89 4-F-Ph H NHEt O 2 90 4-F-Ph HN (Me) _Two O 2 91 4-F-Ph H Pip (1) O 2 92 4-F-Ph H Mor (4) O 2 93 2,4-diF-Ph H NH _Two O 2 94 2,4-diF-Ph F NH _Two O 2 95 2,4-diF-Ph Cl NH _Two O 2 96 2,4-diF-Ph Me NH _Two O 2 97 2,4-diF-Ph Et NH _Two O 2 98 2,4-diF-Ph Pr NH _Two O 2 99 2,4-diF-Ph Pr ⁱ NH _Two O 2 100 2,4-diF-Ph Bu NH _Two O 2 101 2,4-diF-Ph Bu ⁱ NH _Two O 2 102 2,4-diF-Ph Bu ^s NH _Two O 2 103 2,4-diF-Ph Bu ^t NH _Two O 2 104 2,4-diF-Ph H NH _Two S 2 105 2,4-diF-Ph F NH _Two S 2 106 2,4-diF-Ph Cl NH _Two S 2 107 2,4-diF-Ph Me NH _Two S 2 108 2,4-diF-Ph Et NH _Two S 2 109 2,4-diF-Ph Pr NH _Two S 2 110 2,4-diF-Ph Pr ⁱ NH _Two S 2 111 2-Cl-Ph H NH _Two O 2 112 2-Cl-Ph F NH _Two O 2 113 2-Cl-Ph Cl NH _Two O 2 114 2-Cl-Ph Me NH _Two O 2 115 2-Cl-Ph Et NH _Two O 2 116 2-Cl-Ph Pr NH _Two O 2 117 2-Cl-Ph Pr ⁱ NH _Two O 2 118 2-Cl-Ph H NH _Two S 2 119 2-Cl-Ph F NH _Two S 2 120 2-Cl-Ph Cl NH _Two S 2 121 2-Cl-Ph Me NH _Two S 2 122 2-Cl-Ph Et NH _Two S 2 123 2-Cl-Ph Pr NH _Two S 2 124 2-Cl-Ph Pr ⁱ NH _Two S 2 125 3-Cl-Ph H NH _Two O 2 126 3-Cl-Ph F NH _Two O 2 127 3-Cl-Ph Cl NH _Two O 2 128 3-Cl-Ph Me NH _Two O 2 129 3-Cl-Ph Et NH _Two O 2 130 3-Cl-Ph Pr NH _Two O 2 131 3-Cl-Ph Pr ⁱ NH _Two O 2 132 3-Cl-Ph Bu NH _Two O 2 133 3-Cl-Ph Bu ⁱ NH _Two O 2 134 3-Cl-Ph Bu ^s NH _Two O 2 135 3-Cl-Ph Bu ^t NH _Two O 2 136 3-Cl-Ph H NH _Two S 2 137 3-Cl-Ph F NH _Two S 2 138 3-Cl-Ph Cl NH _Two S 2 139 3-Cl-Ph Me NH _Two S 2 140 3-Cl-Ph Et NH _Two S 2 141 3-Cl-Ph Pr NH _Two S 2 142 3-Cl-Ph Pr ⁱ NH _Two S 2 143 4-Cl-Ph H NH _Two O 2 144 4-Cl-Ph H NH _Two O 3 145 4-Cl-Ph H NH _Two O 4 146 4-Cl-Ph F NH _Two O 2 147 4-Cl-Ph Cl NH _Two O 2 148 4-Cl-Ph Me NH _Two O 2 149 4-Cl-Ph Et NH _Two O 2 150 4-Cl-Ph Pr NH _Two O 2 151 4-Cl-Ph Pr ⁱ NH _Two O 2 152 4-Cl-Ph Bu NH _Two O 2 153 4-Cl-Ph Bu ⁱ NH _Two O 2 154 4-Cl-Ph Bu ^s NH _Two O 2 155 4-Cl-Ph Bu ^t NH _Two O 2 156 4-Cl-Ph H NH _Two S 2 157 4-Cl-Ph H NH _Two S 3 158 4-Cl-Ph H NH _Two S 4 159 4-Cl-Ph F NH _Two S 2 160 4-Cl-Ph Cl NH _Two S 2 161 4-Cl-Ph Me NH _Two S 2 162 4-Cl-Ph Et NH _Two S 2 163 4-Cl-Ph Pr NH _Two S 2 164 4-Cl-Ph Pr ⁱ NH _Two S 2 165 4-Cl-Ph H NHMeO 2 166 4-Cl-Ph H NHEt O 2 167 4-Cl-Ph HN (Me) _Two O 2 168 4-Cl-Ph H Pip (1) O 2 169 4-Cl-Ph H Mor (4) O 2 170 2,4-diCl-Ph H NH _Two O 2 171 2,4-diCl-Ph F NH _Two O 2 172 2,4-diCl-Ph Cl NH _Two O 2 173 2,4-diCl-Ph Me NH _Two O 2 174 2,4-diCl-Ph Et NH _Two O 2 175 2,4-diCl-Ph Pr NH _Two O 2 176 2,4-diCl-Ph Pr ⁱ NH _Two O 2 177 2,4-diCl-Ph Bu NH _Two O 2 178 2,4-diCl-Ph Bu ⁱ NH _Two O 2 179 2,4-diCl-Ph Bu ^s NH _Two O 2 180 2,4-diCl-Ph Bu ^t NH _Two O 2 181 2,4-diCl-Ph H NH _Two S 2 182 2,4-diCl-Ph F NH _Two S 2 183 2,4-diCl-Ph Cl NH _Two S 2 184 2,4-diCl-Ph Me NH _Two S 2 185 2,4-diCl-Ph Et NH _Two S 2 186 2,4-diCl-Ph Pr NH _Two S 2 187 2,4-diCl-Ph Pr ⁱ NH _Two S 2 188 2,6-diCl-Ph H NH _Two O 2 189 2,6-diCl-Ph F NH _Two O 2 190 2,6-diCl-Ph Cl NH _Two O 2 191 2,6-diCl-Ph Me NH _Two O 2 192 2,6-diCl-Ph Et NH _Two O 2 193 2,6-diCl-Ph Pr NH _Two O 2 194 2,6-diCl-Ph Pr ⁱ NH _Two O 2 195 2,6-diCl-Ph Bu NH _Two O 2 196 2,6-diCl-Ph Bu ⁱ NH _Two O 2 197 2,6-diCl-Ph Bu ^s NH _Two O 2 198 2,6-diCl-Ph Bu ^t NH _Two O 2 199 2,6-diCl-Ph H NH _Two S 2 200 2,6-diCl-Ph F NH _Two S 2 201 2,6-diCl-Ph Cl NH _Two S 2 202 2,6-diCl-Ph Me NH _Two S 2 203 2,6-diCl-Ph Et NH _Two S 2 204 2,6-diCl-Ph Pr NH _Two S 2 205 2,6-diCl-Ph Pr ⁱ NH _Two S 2 206 3,5-diCl-Ph H NH _Two O 2 207 3,5-diCl-Ph F NH _Two O 2 208 3,5-diCl-Ph Cl NH _Two O 2 209 3,5-diCl-Ph Me NH _Two O 2 210 3,5-diCl-Ph Et NH _Two O 2 211 3,5-diCl-Ph Pr NH _Two O 2 212 3,5-diCl-Ph Pr ⁱ NH _Two O 2 213 3,5-diCl-Ph Bu NH _Two O 2 214 3,5-diCl-Ph Bu ⁱ NH _Two O 2 215 3,5-diCl-Ph Bu ^s NH _Two O 2 216 3,5-diCl-Ph Bu ^t NH _Two O 2 217 3,5-diCl-Ph H NH _Two S 2 218 3,5-diCl-Ph F NH _Two S 2 219 3,5-diCl-Ph Cl NH _Two S 2 220 3,5-diCl-Ph Me NH _Two S 2 221 3,5-diCl-Ph Et NH _Two S 2 222 3,5-diCl-Ph Pr NH _Two S 2 223 3,5-diCl-Ph Pr ⁱ NH _Two S 2 224 2-Me-Ph H NH _Two O 2 225 2-Me-Ph F NH _Two O 2 226 2-Me-Ph Cl NH _Two O 2 227 2-Me-Ph Me NH _Two O 2 228 2-Me-Ph Et NH _Two O 2 229 2-Me-Ph Pr NH _Two O 2 230 2-Me-Ph Pr ⁱ NH _Two O 2 231 2-Me-Ph Bu NH _Two O 2 232 2-Me-Ph Bu ⁱ NH _Two O 2 233 2-Me-Ph Bu ^s NH _Two O 2 234 2-Me-Ph Bu ^t NH _Two O 2 235 2-Me-Ph H NH _Two S 2 236 2-Me-Ph F NH _Two S 2 237 2-Me-Ph Cl NH _Two S 2 238 2-Me-Ph Me NH _Two S 2 239 2-Me-Ph Et NH _Two S 2 240 2-Me-Ph Pr NH _Two S 2 241 2-Me-Ph Pr ⁱ NH _Two S 2 242 3-Me-Ph H NH _Two O 2 243 3-Me-Ph F NH _Two O 2 244 3-Me-Ph Cl NH _Two O 2 245 3-Me-Ph Me NH _Two O 2 246 3-Me-Ph Et NH _Two O 2 247 3-Me-Ph Pr NH _Two O 2 248 3-Me-Ph Pr ⁱ NH _Two O 2 249 3-Me-Ph Bu NH _Two O 2 250 3-Me-Ph Bu ⁱ NH _Two O 2 251 3-Me-Ph Bu ^s NH _Two O 2 252 3-Me-Ph Bu ^t NH _Two O 2 253 3-Me-Ph H NH _Two S 2 254 3-Me-Ph F NH _Two S 2 255 3-Me-Ph Cl NH _Two S 2 256 3-Me-Ph Me NH _Two S 2 257 3-Me-Ph Et NH _Two S 2 258 3-Me-Ph Pr NH _Two S 2 259 3-Me-Ph Pr ⁱ NH _Two S 2 260 4-Me-Ph H NH _Two O 2 261 4-Me-Ph F NH _Two O 2 262 4-Me-Ph Cl NH _Two O 2 263 4-Me-Ph Me NH _Two O 2 264 4-Me-Ph Et NH _Two O 2 265 4-Me-Ph Pr NH _Two O 2 266 4-Me-Ph Pr ⁱ NH _Two O 2 267 4-Me-Ph Bu NH _Two O 2 268 4-Me-Ph Bu ⁱ NH _Two O 2 269 4-Me-Ph Bu ^s NH _Two O 2 270 4-Me-Ph Bu ^t NH _Two O 2 271 4-Me-Ph H NH _Two S 2 272 4-Me-Ph F NH _Two S 2 273 4-Me-Ph Cl NH _Two S 2 274 4-Me-Ph Me NH _Two S 2 275 4-Me-Ph Et NH _Two S 2 276 4-Me-Ph Pr NH _Two S 2 277 4-Me-Ph Pr ⁱ NH _Two S 2 278 4-Et-Ph H NH _Two O 2 279 4-Et-Ph F NH _Two O 2 280 4-Et-Ph Cl NH _Two O 2 281 4-Et-Ph Me NH _Two O 2 282 4-Et-Ph Et NH _Two O 2 283 4-Et-Ph Pr NH _Two O 2 284 4-Et-Ph Pr ⁱ NH _Two O 2 285 4-Et-Ph Bu NH _Two O 2 286 4-Et-Ph Bu ⁱ NH _Two O 2 287 4-Et-Ph Bu ^s NH _Two O 2 288 4-Et-Ph Bu ^t NH _Two O 2 289 4-Et-Ph H NH _Two S 2 290 4-Et-Ph F NH _Two S 2 291 4-Et-Ph Cl NH _Two S 2 292 4-Et-Ph Me NH _Two S 2 293 4-Et-Ph Et NH _Two S 2 294 4-Et-Ph Pr NH _Two S 2 295 4-Et-Ph Pr ⁱ NH _Two S 2 296 2-CF _Three -Ph H NH _Two O 2 297 2-CF _Three -Ph F NH _Two O 2 298 2-CF _Three -Ph Cl NH _Two O 2 299 2-CF _Three -Ph Me NH _Two O 2 300 2-CF _Three -Ph Et NH _Two O 2 301 2-CF _Three -Ph Pr NH _Two O 2 302 2-CF _Three -Ph Pr ⁱ NH _Two O 2 303 2-CF _Three -Ph Bu NH _Two O 2 304 2-CF _Three -Ph Bu ⁱ NH _Two O 2 305 2-CF _Three -Ph Bu ^s NH _Two O 2 306 2-CF _Three -Ph Bu ^t NH _Two O 2 307 2-CF _Three -Ph H NH _Two S 2 308 2-CF _Three -Ph F NH _Two S 2 309 2-CF _Three -Ph Cl NH _Two S 2 310 2-CF _Three -Ph Me NH _Two S 2 311 2-CF _Three -Ph Et NH _Two S 2 312 2-CF _Three -Ph Pr NH _Two S 2 313 2-CF _Three -Ph Pr ⁱ NH _Two S 2 314 3-CF _Three -Ph H NH _Two O 2 315 3-CF _Three -Ph F NH _Two O 2 316 3-CF _Three -Ph Cl NH _Two O 2 317 3-CF _Three -Ph Me NH _Two O 2 318 3-CF _Three -Ph Et NH _Two O 2 319 3-CF _Three -Ph Pr NH _Two O 2 320 3-CF _Three -Ph Pr ⁱ NH _Two O 2 321 3-CF _Three -Ph Bu NH _Two O 2 322 3-CF _Three -Ph Bu ⁱ NH _Two O 2 323 3-CF _Three -Ph Bu ^s NH _Two O 2 324 3-CF _Three -Ph Bu ^t NH _Two O 2 325 3-CF _Three -Ph H NH _Two S 2 326 3-CF _Three -Ph F NH _Two S 2 327 3-CF _Three -Ph Cl NH _Two S 2 328 3-CF _Three -Ph Me NH _Two S 2 329 3-CF _Three -Ph Et NH _Two S 2 330 3-CF _Three -Ph Pr NH _Two S 2 331 3-CF _Three -Ph Pr ⁱ NH _Two S 2 332 4-CF _Three -Ph H NH _Two O 2 333 4-CF _Three -Ph F NH _Two O 2 334 4-CF _Three -Ph Cl NH _Two O 2 335 4-CF _Three -Ph Me NH _Two O 2 336 4-CF _Three -Ph Et NH _Two O 2 337 4-CF _Three -Ph Pr NH _Two O 2 338 4-CF _Three -Ph Pr ⁱ NH _Two O 2 339 4-CF _Three -Ph Bu NH _Two O 2 340 4-CF _Three -Ph Bu ⁱ NH _Two O 2 341 4-CF _Three -Ph Bu ^s NH _Two O 2 342 4-CF _Three -Ph Bu ^t NH _Two O 2 343 4-CF _Three -Ph H NH _Two S 2 344 4-CF _Three -Ph F NH _Two S 2 345 4-CF _Three -Ph Cl NH _Two S 2 346 4-CF _Three -Ph Me NH _Two S 2 347 4-CF _Three -Ph Et NH _Two S 2 348 4-CF _Three -Ph Pr NH _Two S 2 349 4-CF _Three -Ph Pr ⁱ NH _Two S 2 350 4-MeO-Ph H NH _Two O 2 351 4-MeO-Ph F NH _Two O 2 352 4-MeO-Ph Cl NH _Two O 2 353 4-MeO-Ph Me NH _Two O 2 354 4-MeO-Ph Et NH _Two O 2 355 4-MeO-Ph Pr NH _Two O 2 356 4-MeO-Ph Pr ⁱ NH _Two O 2 357 2-MeO-Ph H NH _Two O 2 358 2-MeO-Ph F NH _Two O 2 359 2-MeO-Ph Cl NH _Two O 2 360 2-MeO-Ph Me NH _Two O 2 361 2-MeO-Ph Et NH _Two O 2 362 2-MeO-Ph Pr ⁱ NH _Two O 2 363 3-MeO-Ph H NH _Two O 2 364 3-MeO-Ph Cl NH _Two O 2 365 3-MeO-Ph Me NH _Two O 2 366 3-MeO-Ph Et NH _Two O 2 367 3-MeO-Ph Pr ⁱ NH _Two O 2 368 4-Ph-Ph H NH _Two O 2 369 4-Ph-Ph F NH _Two O 2 370 4-Ph-Ph Cl NH _Two O 2 371 4-Ph-Ph Me NH _Two O 2 372 4-Ph-Ph Et NH _Two O 2 373 4-Ph-Ph Pr NH _Two O 2 374 4-Ph-Ph Pr ⁱ NH _Two O 2 375 4-Ph-Ph Bu NH _Two O 2 376 4-Ph-Ph Bu ⁱ NH _Two O 2 377 4-Ph-Ph Bu ^s NH _Two O 2 378 4-Ph-Ph Bu ^t NH _Two O 2 379 2-Ph-Ph H NH _Two S 2 380 3-Ph-Ph F NH _Two S 2 381 4-Ph-Ph Cl NH _Two S 2 382 2-Ph-Ph Me NH _Two S 2 383 2-Ph-Ph Et NH _Two S 2 384 2-Ph-Ph Pr NH _Two S 2 385 3-Ph-Ph Pr ⁱ NH _Two S 2 386 4-CN-Ph H NH _Two O 2 387 4-CN-Ph F NH _Two O 2 388 4-CN-Ph Cl NH _Two O 2 389 4-CN-Ph Me NH _Two O 2 390 4-CN-Ph Et NH _Two O 2 391 4-CN-Ph Pr NH _Two O 2 392 4-CN-Ph Pr ⁱ NH _Two O 2 393 4-CN-Ph Bu NH _Two O 2 394 4-CN-Ph Bu ⁱ NH _Two O 2 395 4-CN-Ph Bu ^s NH _Two O 2 396 4-CN-Ph Bu ^t NH _Two O 2 397 4-MeOCO-Ph H NH _Two O 2 398 4-MeOCO-Ph F NH _Two O 2 399 4-MeOCO-Ph Cl NH _Two O 2 400 4-MeOCO-Ph Me NH _Two O 2 401 4-MeOCO-Ph Et NH _Two O 2 402 4-MeOCO-Ph Pr NH _Two O 2 403 4-MeOCO-Ph Pr ⁱ NH _Two O 2 404 4-MeOCO-Ph Bu NH _Two O 2 405 4-MeOCO-Ph Bu ⁱ NH _Two O 2 406 4-MeOCO-Ph Bu ^s NH _Two O 2 407 4-MeOCO-Ph Bu ^t NH _Two O 2 408 2-MeOCO-Ph H NH _Two S 2 409 3-MeOCO-Ph F NH _Two S 2 410 4-MeOCO-Ph Cl NH _Two S 2 411 2-MeOCO-Ph Me NH _Two S 2 412 2-MeOCO-Ph Et NH _Two S 2 413 2-MeOCO-Ph Pr NH _Two S 2 414 3-MeOCO-Ph Pr ⁱ NH _Two S 2 415 4-H _Two NCO-Ph H NH _Two O 2 416 4-H _Two NCO-Ph F NH _Two O 2 417 4-H _Two NCO-Ph Cl NH _Two O 2 418 4-H _Two NCO-Ph Me NH _Two O 2 419 4-H _Two NCO-Ph Et NH _Two O 2 420 4-H _Two NCO-Ph Pr NH _Two O 2 421 4-H _Two NCO-Ph Pr ⁱ NH _Two O 2 422 4-H _Two NCO-Ph Bu NH _Two O 2 423 4-H _Two NCO-Ph Bu ⁱ NH _Two O 2 424 4-H _Two NCO-Ph Bu ^s NH _Two O 2 425 4-H _Two NCO-Ph Bu ^t NH _Two O 2 426 2-H _Two NCO-Ph H NH _Two S 2 427 3-H _Two NCO-Ph F NH _Two S 2 428 4-H _Two NCO-Ph Cl NH _Two S 2 429 2-H _Two NCO-Ph Me NH _Two S 2 430 2-H _Two NCO-Ph Et NH _Two S 2 431 2-H _Two NCO-Ph Pr NH _Two S 2 432 3-H _Two NCO-Ph Pr ⁱ NH _Two S 2 433 4-MeNHCO-Ph H NH _Two O 2 434 4-MeNHCO-Ph F NH _Two O 2 435 4-MeNHCO-Ph Cl NH _Two O 2 436 4-MeNHCO-Ph Me NH _Two O 2 437 4-MeNHCO-Ph Et NH _Two O 2 438 4-MeNHCO-Ph Pr NH _Two O 2 439 4-MeNHCO-Ph Pr ⁱ NH _Two O 2 440 4-MeNHCO-Ph Bu NH _Two O 2 441 4-MeNHCO-Ph Bu ⁱ NH _Two O 2 442 4-MeNHCO-Ph Bu ^s NH _Two O 2 443 4-MeNHCO-Ph Bu ^t NH _Two O 2 444 2-MeNHCO-Ph H NH _Two S 2 445 3-MeNHCO-Ph F NH _Two S 2 446 4-MeNHCO-Ph Cl NH _Two S 2 447 2-MeNHCO-Ph Me NH _Two S 2 448 2-MeNHCO-Ph Et NH _Two S 2 449 2-MeNHCO-Ph Pr NH _Two S 2 450 3-MeNHCO-Ph Pr ⁱ NH _Two S 2 451 4- (Me) _Two NCO-Ph H NH _Two O 2 452 4- (Me) _Two NCO-Ph F NH _Two O 2 453 4- (Me) _Two NCO-Ph Cl NH _Two O 2 454 4- (Me) _Two NCO-Ph Me NH _Two O 2 455 4- (Me) _Two NCO-Ph Et NH _Two O 2 456 4- (Me) _Two NCO-Ph Pr NH _Two O 2 457 4- (Me) _Two NCO-Ph Pr ⁱ NH _Two O 2 458 4- (Me) _Two NCO-Ph Bu NH _Two O 2 459 4- (Me) _Two NCO-Ph Bu ⁱ NH _Two O 2 460 4- (Me) _Two NCO-Ph Bu ^s NH _Two O 2 461 4- (Me) _Two NCO-Ph Bu ^t NH _Two O 2 462 2- (Me) _Two NCO-Ph H NH _Two S 2 463 3- (Me) _Two NCO-Ph F NH _Two S 2 464 4- (Me) _Two NCO-Ph Cl NH _Two S 2 465 2- (Me) _Two NCO-Ph Me NH _Two S 2 466 2- (Me) _Two NCO-Ph Et NH _Two S 2 467 2- (Me) _Two NCO-Ph Pr NH _Two S 2 468 3- (Me) _Two NCO-Ph Pr ⁱ NH _Two S 2 (Continuation of Table 1) Compound number R ¹ R ^Two R ^Three X n 469 Inde (1) H NH _Two O 2 470 Inde (1) Cl NH _Two O 2 471 Inde (1) Me NH _Two O 2 472 Inde (1) Et NH _Two O 2 473 Inde (1) Pr NH _Two O 2 474 Inde (1) Pr ⁱ NH _Two O 2 475 Np (1) H NH _Two O 2 476 Np (1) Cl NH _Two O 2 477 Np (1) Me NH _Two O 2 478 Np (1) Et NH _Two O 2 479 Np (1) Pr NH _Two O 2 480 Np (1) Pr ⁱ NH _Two O 2 481 Np (2) H NH _Two O 2 482 Np (2) Cl NH _Two O 2 483 Np (2) Me NH _Two O 2 484 Np (2) Et NH _Two O 2 485 Np (2) Pr NH _Two O 2 486 Np (2) Pr ⁱ NH _Two O 2 487 Pyrr (3) H NH _Two O 2 488 Pyrr (3) Cl NH _Two O 2 489 Pyrr (3) Me NH _Two O 2 490 Pyrr (3) Et NH _Two O 2 491 Pyrr (3) Pr NH _Two O 2 492 Pyrr (3) Pr ⁱ NH _Two O 2 493 Imid (2) H NH _Two O 2 494 Imid (2) Cl NH _Two O 2 495 Imid (2) Me NH _Two O 2 496 Imid (2) Et NH _Two O 2 497 Imid (2) Pr NH _Two O 2 498 Imid (2) Pr ⁱ NH _Two O 2 499 Pyza (1) H NH _Two O 2 500 Pyza (1) Cl NH _Two O 2 501 Pyza (1) Me NH _Two O 2 502 Pyza (1) Et NH _Two O 2 503 Pyza (1) Pr NH _Two O 2 504 Pyza (1) Pr ⁱ NH _Two O 2 505 Fur (2) H NH _Two O 2 506 Fur (2) Cl NH _Two O 2 507 Fur (2) Me NH _Two O 2 508 Fur (2) Et NH _Two O 2 509 Fur (2) Pr NH _Two O 2 510 Fur (2) Pr ⁱ NH _Two O 2 511 Oxa (2) H NH _Two O 2 512 Oxa (2) Cl NH _Two O 2 513 Oxa (2) Me NH _Two O 2 514 Oxa (2) Et NH _Two O 2 515 Oxa (2) Pr NH _Two O 2 516 Oxa (2) Pr ⁱ NH _Two O 2 517 Isox (3) H NH _Two O 2 518 Isox (3) Cl NH _Two O 2 519 Isox (3) Me NH _Two O 2 520 Isox (3) Et NH _Two O 2 521 Isox (3) Pr NH _Two O 2 522 Isox (3) Pr ⁱ NH _Two O 2 523 Thiz (2) H NH _Two O 2 524 Thiz (2) Cl NH _Two O 2 525 Thiz (2) Me NH _Two O 2 526 Thiz (2) Et NH _Two O 2 527 Thiz (2) Pr NH _Two O 2 528 Thiz (2) Pr ⁱ NH _Two O 2 529 Isothiz (3) H NH _Two O 2 530 Isothiz (3) Cl NH _Two O 2 531 Isothiz (3) Me NH _Two O 2 532 Isothiz (3) Et NH _Two O 2 533 Isothiz (3) Pr NH _Two O 2 534 Isothiz (3) Pr ⁱ NH _Two O 2 535 Thi (2) H NH _Two O 2 536 Thi (2) H NH _Two O 3 537 Thi (2) H NH _Two O 4 538 Thi (2) F NH _Two O 2 539 Thi (2) Cl NH _Two O 2 540 Thi (2) Me NH _Two O 2 541 Thi (2) Et NH _Two O 2 542 Thi (2) Pr NH _Two O 2 543 Thi (2) Pr ⁱ NH _Two O 2 544 Thi (2) Bu NH _Two O 2 545 Thi (2) Bu ⁱ NH _Two O 2 546 Thi (2) Bu ^s NH _Two O 2 547 Thi (2) Bu ^t NH _Two O 2 548 Thi (2) H NH _Two S 2 549 Thi (2) H NH _Two S 3 550 Thi (2) H NH _Two S 4 551 Thi (2) F NH _Two S 2 552 Thi (2) Cl NH _Two S 2 553 Thi (2) Me NH _Two S 2 554 Thi (2) Et NH _Two S 2 555 Thi (2) Pr NH _Two S 2 556 Thi (2) Pr ⁱ NH _Two S 2 557 Thi (2) H NHMe O 2 558 Thi (2) H NHEt O 2 559 Thi (2) HN (Me) _Two O 2 560 Thi (2) H Pip (1) O 2 561 Thi (2) H Mor (4) O 2 562 3-F-Thi (2) H NH _Two O 2 563 3-F-Thi (2) Cl NH _Two O 2 564 3-F-Thi (2) Me NH _Two O 2 565 3-F-Thi (2) Et NH _Two O 2 566 3-F-Thi (2) Pr NH _Two O 2 567 3-F-Thi (2) Pr ⁱ NH _Two O 2 568 4-F-Thi (2) H NH _Two O 2 569 4-F-Thi (2) Cl NH _Two O 2 570 4-F-Thi (2) Me NH _Two O 2 571 4-F-Thi (2) Et NH _Two O 2 572 4-F-Thi (2) Pr NH _Two O 2 573 4-F-Thi (2) Pr ⁱ NH _Two O 2 574 5-F-Thi (2) H NH _Two O 2 575 5-F-Thi (2) Cl NH _Two O 2 576 5-F-Thi (2) Me NH _Two O 2 577 5-F-Thi (2) Et NH _Two O 2 578 5-F-Thi (2) Pr NH _Two O 2 579 5-F-Thi (2) Pr ⁱ NH _Two O 2 580 3-Cl-Thi (2) H NH _Two O 2 581 3-Cl-Thi (2) Cl NH _Two O 2 582 3-Cl-Thi (2) Me NH _Two O 2 583 3-Cl-Thi (2) Et NH _Two O 2 584 3-Cl-Thi (2) Pr NH _Two O 2 585 3-Cl-Thi (2) Pr ⁱ NH _Two O 2 586 4-Cl-Thi (2) H NH _Two O 2 587 4-Cl-Thi (2) Cl NH _Two O 2 588 4-Cl-Thi (2) Me NH _Two O 2 589 4-Cl-Thi (2) Et NH _Two O 2 590 4-Cl-Thi (2) Pr NH _Two O 2 591 4-Cl-Thi (2) Pr ⁱ NH _Two O 2 592 5-Cl-Thi (2) H NH _Two O 2 593 5-Cl-Thi (2) Cl NH _Two O 2 594 5-Cl-Thi (2) Me NH _Two O 2 595 5-Cl-Thi (2) Et NH _Two O 2 596 5-Cl-Thi (2) Pr NH _Two O 2 597 5-Cl-Thi (2) Pr ⁱ NH _Two O 2 598 3-Br-Thi (2) H NH _Two O 2 599 3-Br-Thi (2) Cl NH _Two O 2 600 3-Br-Thi (2) Me NH _Two O 2 601 3-Br-Thi (2) Et NH _Two O 2 602 3-Br-Thi (2) Pr NH _Two O 2 603 3-Br-Thi (2) Pr ⁱ NH _Two O 2 604 3-Me-Thi (2) H NH _Two O 2 605 3-Me-Thi (2) Cl NH _Two O 2 606 3-Me-Thi (2) Me NH _Two O 2 607 3-Me-Thi (2) Et NH _Two O 2 608 3-Me-Thi (2) Pr NH _Two O 2 609 3-Me-Thi (2) Pr ⁱ NH _Two O 2 610 4-Me-Thi (2) H NH _Two O 2 611 4-Me-Thi (2) Cl NH _Two O 2 612 4-Me-Thi (2) Me NH _Two O 2 613 4-Me-Thi (2) Et NH _Two O 2 614 4-Me-Thi (2) Pr NH _Two O 2 615 4-Me-Thi (2) Pr ⁱ NH _Two O 2 616 4-Et-Thi (2) H NH _Two O 2 617 4-Et-Thi (2) Cl NH _Two O 2 618 4-Et-Thi (2) Me NH _Two O 2 619 4-Et-Thi (2) Et NH _Two O 2 620 4-Et-Thi (2) Pr NH _Two O 2 622 4-CF _Three -Thi (2) H NH _Two O 2 623 4-CF _Three -Thi (2) Cl NH _Two O 2 624 4-CF _Three -Thi (2) Me NH _Two O 2 625 4-CF _Three -Thi (2) Et NH _Two O 2 626 4-CF _Three -Thi (2) Pr NH _Two O 2 627 4-CF _Three -Thi (2) Pr ⁱ NH _Two O 2 628 4-MeO-Thi (2) H NH _Two O 2 629 4-MeO-Thi (2) Cl NH _Two O 2 630 4-MeO-Thi (2) Me NH _Two O 2 631 4-MeO-Thi (2) Et NH _Two O 2 632 4-MeO-Thi (2) Pr NH _Two O 2 633 4-MeO-Thi (2) Pr ⁱ NH _Two O 2 634 3-Ph-Thi (2) H NH _Two O 2 635 3-Ph-Thi (2) Cl NH _Two O 2 636 3-Ph-Thi (2) Me NH _Two O 2 637 3-Ph-Thi (2) Et NH _Two O 2 638 3-Ph-Thi (2) Pr NH _Two O 2 639 3-Ph-Thi (2) Pr ⁱ NH _Two O 2 640 4-Ph-Thi (2) H NH _Two O 2 641 4-Ph-Thi (2) Cl NH _Two O 2 642 4-Ph-Thi (2) Me NH _Two O 2 643 4-Ph-Thi (2) Et NH _Two O 2 644 4-Ph-Thi (2) Pr NH _Two O 2 645 4-Ph-Thi (2) Pr ⁱ NH _Two O 2 646 5-Ph-Thi (2) H NH _Two O 2 647 5-Ph-Thi (2) Cl NH _Two O 2 648 5-Ph-Thi (2) Me NH _Two O 2 649 5-Ph-Thi (2) Et NH _Two O 2 650 5-Ph-Thi (2) Pr NH _Two O 2 651 5-Ph-Thi (2) Pr ⁱ NH _Two O 2 652 3-MeOCO-Thi (2) H NH _Two O 2 653 3-MeOCO-Thi (2) Cl NH _Two O 2 654 3-MeOCO-Thi (2) Me NH _Two O 2 655 3-MeOCO-Thi (2) Et NH _Two O 2 656 3-MeOCO-Thi (2) Pr NH _Two O 2 657 3-MeOCO-Thi (2) Pr ⁱ NH _Two O 2 658 4-MeOCO-Thi (2) H NH _Two O 2 659 4-MeOCO-Thi (2) Cl NH _Two O 2 660 4-MeOCO-Thi (2) Me NH _Two O 2 661 4-MeOCO-Thi (2) Et NH _Two O 2 662 4-MeOCO-Thi (2) Pr NH _Two O 2 663 4-MeOCO-Thi (2) Pr ⁱ NH _Two O 2 664 5-MeOCO-Thi (2) H NH _Two O 2 665 5-MeOCO-Thi (2) Cl NH _Two O 2 666 5-MeOCO-Thi (2) Me NH _Two O 2 667 5-MeOCO-Thi (2) Et NH _Two O 2 668 5-MeOCO-Thi (2) Pr NH _Two O 2 669 5-MeOCO-Thi (2) Pr ⁱ NH _Two O 2 670 3-H _Two NCO-Thi (2) H NH _Two O 2 671 3-H _Two NCO-Thi (2) Cl NH _Two O 2 672 3-H _Two NCO-Thi (2) Me NH _Two O 2 673 3-H _Two NCO-Thi (2) Et NH _Two O 2 674 3-H _Two NCO-Thi (2) Pr NH _Two O 2 675 3-H _Two NCO-Thi (2) Pr ⁱ NH _Two O 2 676 4-H _Two NCO-Thi (2) H NH _Two O 2 677 4-H _Two NCO-Thi (2) Cl NH _Two O 2 678 4-H _Two NCO-Thi (2) Me NH _Two O 2 679 4-H _Two NCO-Thi (2) Et NH _Two O 2 680 4-H _Two NCO-Thi (2) Pr NH _Two O 2 681 4-H _Two NCO-Thi (2) Pr ⁱ NH _Two O 2 682 5-H _Two NCO-Thi (2) H NH _Two O 2 683 5-H _Two NCO-Thi (2) Cl NH _Two O 2 684 5-H _Two NCO-Thi (2) Me NH _Two O 2 685 5-H _Two NCO-Thi (2) Et NH _Two O 2 686 5-H _Two NCO-Thi (2) Pr NH _Two O 2 687 5-H _Two NCO-Thi (2) Pr ⁱ NH _Two O 2 688 3-MeNHCO-Thi (2) H NH _Two O 2 689 3-MeNHCO-Thi (2) Cl NH _Two O 2 690 3-MeNHCO-Thi (2) Me NH _Two O 2 691 3-MeNHCO-Thi (2) Et NH _Two O 2 692 3-MeNHCO-Thi (2) Pr NH _Two O 2 693 3-MeNHCO-Thi (2) Pr ⁱ NH _Two O 2 694 4-MeNHCO-Thi (2) H NH _Two O 2 695 4-MeNHCO-Thi (2) Cl NH _Two O 2 696 4-MeNHCO-Thi (2) Me NH _Two O 2 697 4-MeNHCO-Thi (2) Et NH _Two O 2 698 4-MeNHCO-Thi (2) Pr NH _Two O 2 699 4-MeNHCO-Thi (2) Pr ⁱ NH _Two O 2 700 5-MeNHCO-Thi (2) H NH _Two O 2 701 5-MeNHCO-Thi (2) Cl NH _Two O 2 702 5-MeNHCO-Thi (2) Me NH _Two O 2 703 5-MeNHCO-Thi (2) Et NH _Two O 2 704 5-MeNHCO-Thi (2) Pr NH _Two O 2 705 5-MeNHCO-Thi (2) Pr ⁱ NH _Two O 2 706 3- (Me) _Two NCO-Thi (2) H NH _Two O 2 707 3- (Me) _Two NCO-Thi (2) Cl NH _Two O 2 708 3- (Me) _Two NCO-Thi (2) Me NH _Two O 2 709 3- (Me) _Two NCO-Thi (2) Et NH _Two O 2 710 3- (Me) _Two NCO-Thi (2) Pr NH _Two O 2 711 3- (Me) _Two NCO-Thi (2) Pr ⁱ NH _Two O 2 712 4- (Me) _Two NCO-Thi (2) H NH _Two O 2 713 4- (Me) _Two NCO-Thi (2) Cl NH _Two O 2 714 4- (Me) _Two NCO-Thi (2) Me NH _Two O 2 715 4- (Me) _Two NCO-Thi (2) Et NH _Two O 2 716 4- (Me) _Two NCO-Thi (2) Pr NH _Two O 2 717 4- (Me) _Two NCO-Thi (2) Pr ⁱ NH _Two O 2 718 5- (Me) _Two NCO-Thi (2) H NH _Two O 2 719 5- (Me) _Two NCO-Thi (2) Cl NH _Two O 2 720 5- (Me) _Two NCO-Thi (2) Me NH _Two O 2 721 5- (Me) _Two NCO-Thi (2) Et NH _Two O 2 722 5- (Me) _Two NCO-Thi (2) Pr NH _Two O 2 723 5- (Me) _Two NCO-Thi (2) Pr ⁱ NH _Two O 2 724 Thi (3) H NH _Two O 2 725 Thi (3) H NH _Two O 3 726 Thi (3) H NH _Two O 4 727 Thi (3) H NH _Two O 5 728 Thi (3) F NH _Two O 2 729 Thi (3) Cl NH _Two O 2 730 Thi (3) Me NH _Two O 2 731 Thi (3) Et NH _Two O 2 732 Thi (3) Pr NH _Two O 2 733 Thi (3) Pr ⁱ NH _Two O 2 734 Thi (3) Bu NH _Two O 2 735 Thi (3) Bu ⁱ NH _Two O 2 736 Thi (3) Bu ^s NH _Two O 2 737 Thi (3) Bu ^t NH _Two O 2 738 Thi (3) H NH _Two S 2 739 Thi (3) H NH _Two S 3 740 Thi (3) H NH _Two S 4 741 Thi (3) F NH _Two S 2 742 Thi (3) Cl NH _Two S 2 743 Thi (3) Me NH _Two S 2 744 Thi (3) Et NH _Two S 2 745 Thi (3) Pr NH _Two S 2 746 Thi (3) Pr ⁱ NH _Two S 2 747 Thi (3) H NHMe O 2 748 Thi (3) H NHEt O 2 749 Thi (3) HN (Me) _Two O 2 750 Thi (3) H Pip (1) O 2 751 Thi (3) H Mor (4) O 2 752 2-F-Thi (3) H NH _Two O 2 753 2-F-Thi (3) Cl NH _Two O 2 754 2-F-Thi (3) Me NH _Two O 2 755 2-F-Thi (3) Et NH _Two O 2 756 2-F-Thi (3) Pr NH _Two O 2 757 2-F-Thi (3) Pr ⁱ NH _Two O 2 758 2-F-Thi (3) H NH _Two S 2 759 2-F-Thi (3) Cl NH _Two S 2 760 2-F-Thi (3) Me NH _Two S 2 761 2-F-Thi (3) Et NH _Two S 2 762 2-F-Thi (3) Pr NH _Two S 2 763 2-F-Thi (3) Pr ⁱ NH _Two S 2 764 4-F-Thi (3) H NH _Two O 2 765 4-F-Thi (3) Cl NH _Two O 2 766 4-F-Thi (3) Me NH _Two O 2 767 4-F-Thi (3) Et NH _Two O 2 768 4-F-Thi (3) Pr NH _Two O 2 769 4-F-Thi (3) Pr ⁱ NH _Two O 2 770 4-F-Thi (3) H NH _Two S 2 771 4-F-Thi (3) Cl NH _Two S 2 772 4-F-Thi (3) Me NH _Two S 2 773 4-F-Thi (3) Et NH _Two S 2 774 4-F-Thi (3) Pr NH _Two S 2 775 4-F-Thi (3) Pr ⁱ NH _Two S 2 776 5-F-Thi (3) H NH _Two O 2 777 5-F-Thi (3) Cl NH _Two O 2 778 5-F-Thi (3) Me NH _Two O 2 779 5-F-Thi (3) Et NH _Two O 2 780 5-F-Thi (3) Pr NH _Two O 2 781 5-F-Thi (3) Pr ⁱ NH _Two O 2 782 5-F-Thi (3) H NH _Two S 2 783 5-F-Thi (3) Cl NH _Two S 2 784 5-F-Thi (3) Me NH _Two S 2 785 5-F-Thi (3) Et NH _Two S 2 786 5-F-Thi (3) Pr NH _Two S 2 787 5-F-Thi (3) Pr ⁱ NH _Two S 2 788 2-Cl-Thi (3) H NH _Two O 2 789 2-Cl-Thi (3) Cl NH _Two O 2 790 2-Cl-Thi (3) Me NH _Two O 2 791 2-Cl-Thi (3) Et NH _Two O 2 792 2-Cl-Thi (3) Pr NH _Two O 2 793 2-Cl-Thi (3) Pr ⁱ NH _Two O 2 794 4-Cl-Thi (3) H NH _Two O 2 795 4-Cl-Thi (3) Cl NH _Two O 2 796 4-Cl-Thi (3) Me NH _Two O 2 797 4-Cl-Thi (3) Et NH _Two O 2 798 4-Cl-Thi (3) Pr NH _Two O 2 799 4-Cl-Thi (3) Pr ⁱ NH _Two O 2 800 5-Cl-Thi (3) H NH _Two O 2 801 5-Cl-Thi (3) Cl NH _Two O 2 802 5-Cl-Thi (3) Me NH _Two O 2 803 5-Cl-Thi (3) Et NH _Two O 2 804 5-Cl-Thi (3) Pr NH _Two O 2 805 5-Cl-Thi (3) Pr ⁱ NH _Two O 2 806 4-Me-Thi (3) H NH _Two O 2 807 4-Me-Thi (3) Cl NH _Two O 2 808 4-Me-Thi (3) Me NH _Two O 2 809 4-Me-Thi (3) Et NH _Two O 2 810 4-Me-Thi (3) Pr NH _Two O 2 811 4-Me-Thi (3) Pr ⁱ NH _Two O 2 812 4-Et-Thi (3) H NH _Two O 2 813 4-Et-Thi (3) Cl NH _Two O 2 814 4-Et-Thi (3) Me NH _Two O 2 815 4-Et-Thi (3) Et NH _Two O 2 816 4-Et-Thi (3) Pr NH _Two O 2 817 4-Et-Thi (3) Pr ⁱ NH _Two O 2 818 4-CF _Three -Thi (3) H NH _Two O 2 819 4-CF _Three -Thi (3) Cl NH _Two O 2 820 4-CF _Three -Thi (3) Me NH _Two O 2 821 4-CF _Three -Thi (3) Et NH _Two O 2 822 4-CF _Three -Thi (3) Pr NH _Two O 2 823 4-CF _Three -Thi (3) Pr ⁱ NH _Two O 2 824 4-MeO-Thi (3) H NH _Two O 2 825 4-MeO-Thi (3) Cl NH _Two O 2 826 4-MeO-Thi (3) Me NH _Two O 2 827 4-MeO-Thi (3) Et NH _Two O 2 828 4-MeO-Thi (3) Pr NH _Two O 2 829 4-MeO-Thi (3) Pr ⁱ NH _Two O 2 830 2-Ph-Thi (3) H NH _Two O 2 831 2-Ph-Thi (3) Cl NH _Two O 2 832 2-Ph-Thi (3) Me NH _Two O 2 833 2-Ph-Thi (3) Et NH _Two O 2 834 2-Ph-Thi (3) Pr NH _Two O 2 835 2-Ph-Thi (3) Pr ⁱ NH _Two O 2 836 4-Ph-Thi (3) H NH _Two O 2 837 4-Ph-Thi (3) Cl NH _Two O 2 838 4-Ph-Thi (3) Me NH _Two O 2 839 4-Ph-Thi (3) Et NH _Two O 2 840 4-Ph-Thi (3) Pr NH _Two O 2 841 4-Ph-Thi (3) Pr ⁱ NH _Two O 2 842 5-Ph-Thi (3) H NH _Two O 2 843 5-Ph-Thi (3) Cl NH _Two O 2 844 5-Ph-Thi (3) Me NH _Two O 2 845 5-Ph-Thi (3) Et NH _Two O 2 846 5-Ph-Thi (3) Pr NH _Two O 2 847 5-Ph-Thi (3) Pr ⁱ NH _Two O 2 848 2-MeOCO-Thi (3) H NH _Two O 2 849 2-MeOCO-Thi (3) Cl NH _Two O 2 850 2-MeOCO-Thi (3) Me NH _Two O 2 851 2-MeOCO-Thi (3) Et NH _Two O 2 852 2-MeOCO-Thi (3) Pr NH _Two O 2 853 2-MeOCO-Thi (3) Pr ⁱ NH _Two O 2 854 4-MeOCO-Thi (3) H NH _Two O 2 855 4-MeOCO-Thi (3) Cl NH _Two O 2 856 4-MeOCO-Thi (3) Me NH _Two O 2 857 4-MeOCO-Thi (3) Et NH _Two O 2 858 4-MeOCO-Thi (3) Pr NH _Two O 2 859 4-MeOCO-Thi (3) Pr ⁱ NH _Two O 2 860 5-MeOCO-Thi (3) H NH _Two O 2 861 5-MeOCO-Thi (3) Cl NH _Two O 2 862 5-MeOCO-Thi (3) Me NH _Two O 2 863 5-MeOCO-Thi (3) Et NH _Two O 2 864 5-MeOCO-Thi (3) Pr NH _Two O 2 865 5-MeOCO-Thi (3) Pr ⁱ NH _Two O 2 866 2-H _Two NCO-Thi (3) H NH _Two O 2 867 2-H _Two NCO-Thi (3) Cl NH _Two O 2 868 2-H _Two NCO-Thi (3) Me NH _Two O 2 869 2-H _Two NCO-Thi (3) Et NH _Two O 2 870 2-H _Two NCO-Thi (3) Pr NH _Two O 2 871 2-H _Two NCO-Thi (3) Pr ⁱ NH _Two O 2 872 4-H _Two NCO-Thi (3) H NH _Two O 2 873 4-H _Two NCO-Thi (3) Cl NH _Two O 2 874 4-H _Two NCO-Thi (3) Me NH _Two O 2 875 4-H _Two NCO-Thi (3) Et NH _Two O 2 876 4-H _Two NCO-Thi (3) Pr NH _Two O 2 877 4-H _Two NCO-Thi (3) Pr ⁱ NH _Two O 2 878 5-H _Two NCO-Thi (3) H NH _Two O 2 879 5-H _Two NCO-Thi (3) Cl NH _Two O 2 880 5-H _Two NCO-Thi (3) Me NH _Two O 2 881 5-H _Two NCO-Thi (3) Et NH _Two O 2 882 5-H _Two NCO-Thi (3) Pr NH _Two O 2 883 5-H _Two NCO-Thi (3) Pr ⁱ NH _Two O 2 884 2-MeNHCO-Thi (3) H NH _Two O 2 885 2-MeNHCO-Thi (3) Cl NH _Two O 2 886 2-MeNHCO-Thi (3) Me NH _Two O 2 887 2-MeNHCO-Thi (3) Et NH _Two O 2 888 2-MeNHCO-Thi (3) Pr NH _Two O 2 889 2-MeNHCO-Thi (3) Pr ⁱ NH _Two O 2 890 4-MeNHCO-Thi (3) H NH _Two O 2 891 4-MeNHCO-Thi (3) Cl NH _Two O 2 892 4-MeNHCO-Thi (3) Me NH _Two O 2 893 4-MeNHCO-Thi (3) Et NH _Two O 2 894 4-MeNHCO-Thi (3) Pr NH _Two O 2 895 4-MeNHCO-Thi (3) Pr ⁱ NH _Two O 2 896 5-MeNHCO-Thi (3) H NH _Two O 2 897 5-MeNHCO-Thi (3) Cl NH _Two O 2 898 5-MeNHCO-Thi (3) Me NH _Two O 2 899 5-MeNHCO-Thi (3) Et NH _Two O 2 900 5-MeNHCO-Thi (3) Pr NH _Two O 2 901 5-MeNHCO-Thi (3) Pr ⁱ NH _Two O 2 902 2- (Me) _Two NCO-Thi (3) H NH _Two O 2 903 2- (Me) _Two NCO-Thi (3) Cl NH _Two O 2 904 2- (Me) _Two NCO-Thi (3) Me NH _Two O 2 905 2- (Me) _Two NCO-Thi (3) Et NH _Two O 2 906 2- (Me) _Two NCO-Thi (3) Pr NH _Two O 2 907 2- (Me) _Two NCO-Thi (3) Pr ⁱ NH _Two O 2 908 4- (Me) _Two NCO-Thi (3) H NH _Two O 2 909 4- (Me) _Two NCO-Thi (3) Cl NH _Two O 2 910 4- (Me) _Two NCO-Thi (3) Me NH _Two O 2 911 4- (Me) _Two NCO-Thi (3) Et NH _Two O 2 912 4- (Me) _Two NCO-Thi (3) Pr NH _Two O 2 913 4- (Me) _Two NCO-Thi (3) Pr ⁱ NH _Two O 2 914 5- (Me) _Two NCO-Thi (3) H NH _Two O 2 915 5- (Me) _Two NCO-Thi (3) Cl NH _Two O 2 916 5- (Me) _Two NCO-Thi (3) Me NH _Two O 2 917 5- (Me) _Two NCO-Thi (3) Et NH _Two O 2 918 5- (Me) _Two NCO-Thi (3) Pr NH _Two O 2 919 5- (Me) _Two NCO-Thi (3) Pr ⁱ NH _Two O 2 (Continuation of Table 1) Compound number R ¹ R ^Two R ^Three X n 920 Pyr (2) H NH _Two O 2 921 Pyr (2) H NH _Two O 2 922 Pyr (2) H NH _Two O 3 923 Pyr (2) H NH _Two O 4 924 Pyr (2) F NH _Two O 2 925 Pyr (2) Cl NH _Two O 2 926 Pyr (2) Me NH _Two O 2 927 Pyr (2) Et NH _Two O 2 928 Pyr (2) Pr NH _Two O 2 929 Pyr (2) Pr ⁱ NH _Two O 2 930 Pyr (2) Bu NH _Two O 2 931 Pyr (2) Bu ⁱ NH _Two O 2 932 Pyr (2) Bu ^s NH _Two O 2 933 Pyr (2) Bu ^t NH _Two O 2 934 Pyr (2) H NH _Two S 2 935 Pyr (2) H NH _Two S 3 936 Pyr (2) H NH _Two S 4 937 Pyr (2) F NH _Two S 2 938 Pyr (2) Cl NH _Two S 2 939 Pyr (2) Me NH _Two S 2 940 Pyr (2) Et NH _Two S 2 941 Pyr (2) Pr NH _Two S 2 942 Pyr (2) Pr ⁱ NH _Two S 2 943 Pyr (2) H NHMe O 2 944 Pyr (2) H NHEt O 2 945 Pyr (2) HN (Me) _Two O 2 946 Pyr (2) H Pip (1) O 2 947 Pyr (2) H Mor (4) O 2 948 3-F-Pyr (2) H NH _Two O 2 949 3-F-Pyr (2) Cl NH _Two O 2 950 3-F-Pyr (2) Me NH _Two O 2 951 3-F-Pyr (2) Et NH _Two O 2 952 3-F-Pyr (2) Pr NH _Two O 2 953 3-F-Pyr (2) Pr ⁱ NH _Two O 2 954 4-F-Pyr (2) H NH _Two O 2 955 4-F-Pyr (2) Cl NH _Two O 2 956 4-F-Pyr (2) Me NH _Two O 2 957 4-F-Pyr (2) Et NH _Two O 2 958 4-F-Pyr (2) Pr NH _Two O 2 959 4-F-Pyr (2) Pr ⁱ NH _Two O 2 960 3-Cl-Pyr (2) H NH _Two O 2 961 3-Cl-Pyr (2) Cl NH _Two O 2 962 3-Cl-Pyr (2) Me NH _Two O 2 963 3-Cl-Pyr (2) Et NH _Two O 2 964 3-Cl-Pyr (2) Pr NH _Two O 2 965 3-Cl-Pyr (2) Pr ⁱ NH _Two O 2 966 4-Cl-Pyr (2) H NH _Two O 2 967 4-Cl-Pyr (2) Cl NH _Two O 2 968 4-Cl-Pyr (2) Me NH _Two O 2 969 4-Cl-Pyr (2) Et NH _Two O 2 970 4-Cl-Pyr (2) Pr NH _Two O 2 971 4-Cl-Pyr (2) Pr ⁱ NH _Two O 2 972 4-Me-Pyr (2) H NH _Two O 2 973 4-Me-Pyr (2) Cl NH _Two O 2 974 4-Me-Pyr (2) Me NH _Two O 2 975 4-Me-Pyr (2) Et NH _Two O 2 976 4-Me-Pyr (2) Pr NH _Two O 2 977 4-Me-Pyr (2) Pr ⁱ NH _Two O 2 978 4-Et-Pyr (2) H NH _Two O 2 979 4-Et-Pyr (2) Cl NH _Two O 2 980 4-Et-Pyr (2) Me NH _Two O 2 981 4-Et-Pyr (2) Et NH _Two O 2 982 4-Et-Pyr (2) Pr NH _Two O 2 983 4-Et-Pyr (2) Pr ⁱ NH _Two O 2 984 4-CF _Three -Pyr (2) H NH _Two O 2 985 4-CF _Three -Pyr (2) Cl NH _Two O 2 986 4-CF _Three -Pyr (2) Me NH _Two O 2 987 4-CF _Three -Pyr (2) Et NH _Two O 2 988 4-CF _Three -Pyr (2) Pr NH _Two O 2 989 4-CF _Three -Pyr (2) Pr ⁱ NH _Two O 2 990 4-MeO-Pyr (2) H NH _Two O 2 991 4-MeO-Pyr (2) Cl NH _Two O 2 992 4-MeO-Pyr (2) Me NH _Two O 2 993 4-MeO-Pyr (2) Et NH _Two O 2 994 4-MeO-Pyr (2) Pr NH _Two O 2 995 4-MeO-Pyr (2) Pr ⁱ NH _Two O 2 996 3-Ph-Pyr (2) H NH _Two O 2 997 3-Ph-Pyr (2) Cl NH _Two O 2 998 3-Ph-Pyr (2) Me NH _Two O 2 999 3-Ph-Pyr (2) Et NH _Two O 2 1000 3-Ph-Pyr (2) Pr NH _Two O 2 1001 3-Ph-Pyr (2) Pr ⁱ NH _Two O 2 1002 4-Ph-Pyr (2) H NH _Two O 2 1003 4-Ph-Pyr (2) Cl NH _Two O 2 1004 4-Ph-Pyr (2) Me NH _Two O 2 1005 4-Ph-Pyr (2) Et NH _Two O 2 1006 4-Ph-Pyr (2) Pr NH _Two O 2 1007 4-Ph-Pyr (2) Pr ⁱ NH _Two O 2 1008 3-MeOCO-Pyr (2) H NH _Two O 2 1009 3-MeOCO-Pyr (2) Cl NH _Two O 2 1010 3-MeOCO-Pyr (2) Me NH _Two O 2 1011 3-MeOCO-Pyr (2) Et NH _Two O 2 1012 3-MeOCO-Pyr (2) Pr NH _Two O 2 1013 3-MeOCO-Pyr (2) Pr ⁱ NH _Two O 2 1014 4-MeOCO-Pyr (2) H NH _Two O 2 1015 4-MeOCO-Pyr (2) Cl NH _Two O 2 1016 4-MeOCO-Pyr (2) Me NH _Two O 2 1017 4-MeOCO-Pyr (2) Et NH _Two O 2 1018 4-MeOCO-Pyr (2) Pr NH _Two O 2 1019 4-MeOCO-Pyr (2) Pr ⁱ NH _Two O 2 1020 3-H _Two NCO-Pyr (2) H NH _Two O 2 1021 3-H _Two NCO-Pyr (2) Cl NH _Two O 2 1022 3-H _Two NCO-Pyr (2) Me NH _Two O 2 1023 3-H _Two NCO-Pyr (2) Et NH _Two O 2 1024 3-H _Two NCO-Pyr (2) Pr NH _Two O 2 1025 3-H _Two NCO-Pyr (2) Pr ⁱ NH _Two O 2 1026 4-H _Two NCO-Pyr (2) H NH _Two O 2 1027 4-H _Two NCO-Pyr (2) Cl NH _Two O 2 1028 4-H _Two NCO-Pyr (2) Me NH _Two O 2 1029 4-H _Two NCO-Pyr (2) Et NH _Two O 2 1030 4-H _Two NCO-Pyr (2) Pr NH _Two O 2 1031 4-H _Two NCO-Pyr (2) Pr ⁱ NH _Two O 2 1032 3-MeNHCO-Pyr (2) H NH _Two O 2 1033 3-MeNHCO-Pyr (2) Cl NH _Two O 2 1034 3-MeNHCO-Pyr (2) Me NH _Two O 2 1035 3-MeNHCO-Pyr (2) Et NH _Two O 2 1036 3-MeNHCO-Pyr (2) Pr NH _Two O 2 1037 3-MeNHCO-Pyr (2) Pr ⁱ NH _Two O 2 1038 4-MeNHCO-Pyr (2) H NH _Two O 2 1039 4-MeNHCO-Pyr (2) Cl NH _Two O 2 1040 4-MeNHCO-Pyr (2) Me NH _Two O 2 1041 4-MeNHCO-Pyr (2) Et NH _Two O 2 1042 4-MeNHCO-Pyr (2) Pr NH _Two O 2 1043 4-MeNHCO-Pyr (2) Pr ⁱ NH _Two O 2 1044 3- (Me) _Two NCO-Pyr (2) H NH _Two O 2 1045 3- (Me) _Two NCO-Pyr (2) Cl NH _Two O 2 1046 3- (Me) _Two NCO-Pyr (2) Me NH _Two O 2 1047 3- (Me) _Two NCO-Pyr (2) Et NH _Two O 2 1048 3- (Me) _Two NCO-Pyr (2) Pr NH _Two O 2 1049 3- (Me) _Two NCO-Pyr (2) Pr ⁱ NH _Two O 2 1050 4- (Me) _Two NCO-Pyr (2) H NH _Two O 2 1051 4- (Me) _Two NCO-Pyr (2) Cl NH _Two O 2 1052 4- (Me) _Two NCO-Pyr (2) Me NH _Two O 2 1053 4- (Me) _Two NCO-Pyr (2) Et NH _Two O 2 1054 4- (Me) _Two NCO-Pyr (2) Pr NH _Two O 2 1055 4- (Me) _Two NCO-Pyr (2) Pr ⁱ NH _Two O 2 1056 Pyr (3) H NH _Two O 2 1057 Pyr (3) H NH _Two O 2 1058 Pyr (3) H NH _Two O 3 1059 Pyr (3) H NH _Two O 4 1060 Pyr (3) F NH _Two O 2 1061 Pyr (3) Cl NH _Two O 2 1062 Pyr (3) Me NH _Two O 2 1063 Pyr (3) Et NH _Two O 2 1064 Pyr (3) Pr NH _Two O 2 1065 Pyr (3) Pr ⁱ NH _Two O 2 1066 Pyr (3) Bu NH _Two O 2 1067 Pyr (3) Bu ⁱ NH _Two O 2 1068 Pyr (3) Bu ^s NH _Two O 2 1069 Pyr (3) Bu ^t NH _Two O 2 1070 Pyr (3) H NH _Two S 2 1071 Pyr (3) H NH _Two S 3 1072 Pyr (3) H NH _Two S 4 1073 Pyr (3) F NH _Two S 2 1074 Pyr (3) Cl NH _Two S 2 1075 Pyr (3) Me NH _Two S 2 1076 Pyr (3) Et NH _Two S 2 1077 Pyr (3) Pr NH _Two S 2 1078 Pyr (3) Pr ⁱ NH _Two S 2 1079 Pyr (3) H NHMe O 2 1080 Pyr (3) H NHEt O 2 1081 Pyr (3) HN (Me) _Two O 2 1082 Pyr (3) H Pip (1) O 2 1083 Pyr (3) H Mor (4) O 2 1084 2-F-Pyr (3) H NH _Two O 2 1085 2-F-Pyr (3) Cl NH _Two O 2 1086 2-F-Pyr (3) Me NH _Two O 2 1087 2-F-Pyr (3) Et NH _Two O 2 1088 2-F-Pyr (3) Pr NH _Two O 2 1089 2-F-Pyr (3) Pr ⁱ NH _Two O 2 1090 4-F-Pyr (3) H NH _Two O 2 1091 4-F-Pyr (3) Cl NH _Two O 2 1092 4-F-Pyr (3) Me NH _Two O 2 1093 4-F-Pyr (3) Et NH _Two O 2 1094 4-F-Pyr (3) Pr NH _Two O 2 1095 4-F-Pyr (3) Pr ⁱ NH _Two O 2 1096 2-Cl-Pyr (3) H NH _Two O 2 1097 2-Cl-Pyr (3) Cl NH _Two O 2 1098 2-Cl-Pyr (3) Me NH _Two O 2 1099 2-Cl-Pyr (3) Et NH _Two O 2 1100 2-Cl-Pyr (3) Pr NH _Two O 2 1101 2-Cl-Pyr (3) Pr ⁱ NH _Two O 2 1102 4-Cl-Pyr (3) H NH _Two O 2 1103 4-Cl-Pyr (3) Cl NH _Two O 2 1104 4-Cl-Pyr (3) Me NH _Two O 2 1105 4-Cl-Pyr (3) Et NH _Two O 2 1106 4-Cl-Pyr (3) Pr NH _Two O 2 1107 4-Cl-Pyr (3) Pr ⁱ NH _Two O 2 1108 4-Me-Pyr (3) H NH _Two O 2 1109 4-Me-Pyr (3) Cl NH _Two O 2 1110 4-Me-Pyr (3) Me NH _Two O 2 1111 4-Me-Pyr (3) Et NH _Two O 2 1112 4-Me-Pyr (3) Pr NH _Two O 2 1113 4-Me-Pyr (3) Pr ⁱ NH _Two O 2 1114 4-Et-Pyr (3) H NH _Two O 2 1115 4-Et-Pyr (3) Cl NH _Two O 2 1116 4-Et-Pyr (3) Me NH _Two O 2 1117 4-Et-Pyr (3) Et NH _Two O 2 1118 4-Et-Pyr (3) Pr NH _Two O 2 1119 4-Et-Pyr (3) Pr ⁱ NH _Two O 2 1120 4-CF _Three -Pyr (3) H NH _Two O 2 1121 4-CF _Three -Pyr (3) Cl NH _Two O 2 1122 4-CF _Three -Pyr (3) Me NH _Two O 2 1123 4-CF _Three -Pyr (3) Et NH _Two O 2 1124 4-CF _Three -Pyr (3) Pr NH _Two O 2 1125 4-CF _Three -Pyr (3) Pr ⁱ NH _Two O 2 1126 4-MeO-Pyr (3) H NH _Two O 2 1127 4-MeO-Pyr (3) Cl NH _Two O 2 1128 4-MeO-Pyr (3) Me NH _Two O 2 1129 4-MeO-Pyr (3) Et NH _Two O 2 1130 4-MeO-Pyr (3) Pr NH _Two O 2 1131 4-MeO-Pyr (3) Pr ⁱ NH _Two O 2 1132 2-Ph-Pyr (3) H NH _Two O 2 1133 2-Ph-Pyr (3) Cl NH _Two O 2 1134 2-Ph-Pyr (3) Me NH _Two O 2 1135 2-Ph-Pyr (3) Et NH _Two O 2 1136 2-Ph-Pyr (3) Pr NH _Two O 2 1137 2-Ph-Pyr (3) Pr ⁱ NH _Two O 2 1138 4-Ph-Pyr (3) H NH _Two O 2 1139 4-Ph-Pyr (3) Cl NH _Two O 2 1140 4-Ph-Pyr (3) Me NH _Two O 2 1141 4-Ph-Pyr (3) Et NH _Two O 2 1142 4-Ph-Pyr (3) Pr NH _Two O 2 1143 4-Ph-Pyr (3) Pr ⁱ NH _Two O 2 1144 2-MeOCO-Pyr (3) H NH _Two O 2 1145 2-MeOCO-Pyr (3) Cl NH _Two O 2 1146 2-MeOCO-Pyr (3) Me NH _Two O 2 1147 2-MeOCO-Pyr (3) Et NH _Two O 2 1148 2-MeOCO-Pyr (3) Pr NH _Two O 2 1149 2-MeOCO-Pyr (3) Pr ⁱ NH _Two O 2 1150 4-MeOCO-Pyr (3) H NH _Two O 2 1151 4-MeOCO-Pyr (3) Cl NH _Two O 2 1152 4-MeOCO-Pyr (3) Me NH _Two O 2 1153 4-MeOCO-Pyr (3) Et NH _Two O 2 1154 4-MeOCO-Pyr (3) Pr NH _Two O 2 1155 4-MeOCO-Pyr (3) Pr ⁱ NH _Two O 2 1156 2-H _Two NCO-Pyr (3) H NH _Two O 2 1157 2-H _Two NCO-Pyr (3) Cl NH _Two O 2 1158 2-H _Two NCO-Pyr (3) Me NH _Two O 2 1159 2-H _Two NCO-Pyr (3) Et NH _Two O 2 1160 2-H _Two NCO-Pyr (3) Pr NH _Two O 2 1161 2-H _Two NCO-Pyr (3) Pr ⁱ NH _Two O 2 1162 4-H _Two NCO-Pyr (3) H NH _Two O 2 1163 4-H _Two NCO-Pyr (3) Cl NH _Two O 2 1164 4-H _Two NCO-Pyr (3) Me NH _Two O 2 1165 4-H _Two NCO-Pyr (3) Et NH _Two O 2 1166 4-H _Two NCO-Pyr (3) Pr NH _Two O 2 1167 4-H _Two NCO-Pyr (3) Pr ⁱ NH _Two O 2 1168 2-MeNHCO-Pyr (3) H NH _Two O 2 1169 2-MeNHCO-Pyr (3) Cl NH _Two O 2 1170 2-MeNHCO-Pyr (3) Me NH _Two O 2 1171 2-MeNHCO-Pyr (3) Et NH _Two O 2 1172 2-MeNHCO-Pyr (3) Pr NH _Two O 2 1173 2-MeNHCO-Pyr (3) Pr ⁱ NH _Two O 2 1174 4-MeNHCO-Pyr (3) H NH _Two O 2 1175 4-MeNHCO-Pyr (3) Cl NH _Two O 2 1176 4-MeNHCO-Pyr (3) Me NH _Two O 2 1177 4-MeNHCO-Pyr (3) Et NH _Two O 2 1178 4-MeNHCO-Pyr (3) Pr NH _Two O 2 1179 4-MeNHCO-Pyr (3) Pr ⁱ NH _Two O 2 1180 2- (Me) _Two NCO-Pyr (3) H NH _Two O 2 1181 2- (Me) _Two NCO-Pyr (3) Cl NH _Two O 2 1182 2- (Me) _Two NCO-Pyr (3) Me NH _Two O 2 1183 2- (Me) _Two NCO-Pyr (3) Et NH _Two O 2 1184 2- (Me) _Two NCO-Pyr (3) Pr NH _Two O 2 1185 2- (Me) _Two NCO-Pyr (3) Pr ⁱ NH _Two O 2 1186 4- (Me) _Two NCO-Pyr (3) H NH _Two O 2 1187 4- (Me) _Two NCO-Pyr (3) Cl NH _Two O 2 1188 4- (Me) _Two NCO-Pyr (3) Me NH _Two O 2 1189 4- (Me) _Two NCO-Pyr (3) Et NH _Two O 2 1190 4- (Me) _Two NCO-Pyr (3) Pr NH _Two O 2 1191 4- (Me) _Two NCO-Pyr (3) Pr ⁱ NH _Two O 2 1192 Pyr (4) H NH _Two O 2 1193 Pyr (4) H NH _Two O 2 1194 Pyr (4) H NH _Two O 3 1195 Pyr (4) H NH _Two O 4 1196 Pyr (4) F NH _Two O 2 1197 Pyr (4) Cl NH _Two O 2 1198 Pyr (4) Me NH _Two O 2 1199 Pyr (4) Et NH _Two O 2 1200 Pyr (4) Pr NH _Two O 2 1201 Pyr (4) Pr ⁱ NH _Two O 2 1202 Pyr (4) Bu NH _Two O 2 1203 Pyr (4) Bu ⁱ NH _Two O 2 1204 Pyr (4) Bu ^s NH _Two O 2 1206 Pyr (4) Bu ^t NH _Two O 2 1207 Pyr (4) H NH _Two S 2 1208 Pyr (4) H NH _Two S 3 1209 Pyr (4) H NH _Two S 4 1210 Pyr (4) F NH _Two S 2 1211 Pyr (4) Cl NH _Two S 2 1212 Pyr (4) Me NH _Two S 2 1213 Pyr (4) Et NH _Two S 2 1214 Pyr (4) Pr NH _Two S 2 1215 Pyr (4) Pr ⁱ NH _Two S 2 1216 Pyr (4) H NHMe O 2 1217 Pyr (4) H NHEt O 2 1219 Pyr (4) H Pip (1) O 2 1220 Pyr (4) H Mor (4) O 2 1221 2-F-Pyr (4) H NH _Two O 2 1222 2-F-Pyr (4) Cl NH _Two O 2 1223 2-F-Pyr (4) Me NH _Two O 2 1224 2-F-Pyr (4) Et NH _Two O 2 1225 2-F-Pyr (4) Pr NH _Two O 2 1226 2-F-Pyr (4) Pr ⁱ NH _Two O 2 1227 3-F-Pyr (4) H NH _Two O 2 1228 3-F-Pyr (4) Cl NH _Two O 2 1229 3-F-Pyr (4) Me NH _Two O 2 1230 3-F-Pyr (4) Et NH _Two O 2 1231 3-F-Pyr (4) Pr NH _Two O 2 1232 3-F-Pyr (4) Pr ⁱ NH _Two O 2 1233 2-Cl-Pyr (4) H NH _Two O 2 1234 2-Cl-Pyr (4) Cl NH _Two O 2 1235 2-Cl-Pyr (4) Me NH _Two O 2 1236 2-Cl-Pyr (4) Et NH _Two O 2 1237 2-Cl-Pyr (4) Pr NH _Two O 2 1238 2-Cl-Pyr (4) Pr ⁱ NH _Two O 2 1239 3-Cl-Pyr (4) H NH _Two O 2 1240 3-Cl-Pyr (4) Cl NH _Two O 2 1241 3-Cl-Pyr (4) Me NH _Two O 2 1242 3-Cl-Pyr (4) Et NH _Two O 2 1243 3-Cl-Pyr (4) Pr NH _Two O 2 1244 3-Cl-Pyr (4) Pr ⁱ NH _Two O 2 1245 3-Me-Pyr (4) H NH _Two O 2 1246 3-Me-Pyr (4) Cl NH _Two O 2 1247 3-Me-Pyr (4) Me NH _Two O 2 1248 3-Me-Pyr (4) Et NH _Two O 2 1249 3-Me-Pyr (4) Pr NH _Two O 2 1250 3-Me-Pyr (4) Pr ⁱ NH _Two O 2 1251 3-Et-Pyr (4) H NH _Two O 2 1252 3-Et-Pyr (4) Cl NH _Two O 2 1253 3-Et-Pyr (4) Me NH _Two O 2 1254 3-Et-Pyr (4) Et NH _Two O 2 1255 3-Et-Pyr (4) Pr NH _Two O 2 1256 3-Et-Pyr (4) Pr ⁱ NH _Two O 2 1257 3-CF _Three -Pyr (4) H NH _Two O 2 1258 3-CF _Three -Pyr (4) Cl NH _Two O 2 1259 3-CF _Three -Pyr (4) Me NH _Two O 2 1260 3-CF _Three -Pyr (4) Et NH _Two O 2 1261 3-CF _Three -Pyr (4) Pr NH _Two O 2 1262 3-CF _Three -Pyr (4) Pr ⁱ NH _Two O 2 1263 3-MeO-Pyr (4) H NH _Two O 2 1264 3-MeO-Pyr (4) Cl NH _Two O 2 1265 3-MeO-Pyr (4) Me NH _Two O 2 1266 3-MeO-Pyr (4) Et NH _Two O 2 1267 3-MeO-Pyr (4) Pr NH _Two O 2 1268 3-MeO-Pyr (4) Pr ⁱ NH _Two O 2 1269 2-Ph-Pyr (4) H NH _Two O 2 1270 2-Ph-Pyr (4) Cl NH _Two O 2 1271 2-Ph-Pyr (4) Me NH _Two O 2 1272 2-Ph-Pyr (4) Et NH _Two O 2 1273 2-Ph-Pyr (4) Pr NH _Two O 2 1274 2-Ph-Pyr (4) Pr ⁱ NH _Two O 2 1275 3-Ph-Pyr (4) H NH _Two O 2 1276 3-Ph-Pyr (4) Cl NH _Two O 2 1277 3-Ph-Pyr (4) Me NH _Two O 2 1278 3-Ph-Pyr (4) Et NH _Two O 2 1279 3-Ph-Pyr (4) Pr NH _Two O 2 1280 3-Ph-Pyr (4) Pr ⁱ NH _Two O 2 1281 2-MeOCO-Pyr (4) H NH _Two O 2 1282 2-MeOCO-Pyr (4) Cl NH _Two O 2 1283 2-MeOCO-Pyr (4) Me NH _Two O 2 1284 2-MeOCO-Pyr (4) Et NH _Two O 2 1285 2-MeOCO-Pyr (4) Pr NH _Two O 2 1286 2-MeOCO-Pyr (4) Pr ⁱ NH _Two O 2 1287 3-MeOCO-Pyr (4) H NH _Two O 2 1288 3-MeOCO-Pyr (4) Cl NH _Two O 2 1289 3-MeOCO-Pyr (4) Me NH _Two O 2 1290 3-MeOCO-Pyr (4) Et NH _Two O 2 1291 3-MeOCO-Pyr (4) Pr NH _Two O 2 1292 3-MeOCO-Pyr (4) Pr ⁱ NH _Two O 2 1293 2-H _Two NCO-Pyr (4) H NH _Two O 2 1294 2-H _Two NCO-Pyr (4) Cl NH _Two O 2 1295 2-H _Two NCO-Pyr (4) Me NH _Two O 2 1296 2-H _Two NCO-Pyr (4) Et NH _Two O 2 1297 2-H _Two NCO-Pyr (4) Pr NH _Two O 2 1298 2-H _Two NCO-Pyr (4) Pr ⁱ NH _Two O 2 1299 3-H _Two NCO-Pyr (4) H NH _Two O 2 1300 3-H _Two NCO-Pyr (4) Cl NH _Two O 2 1301 3-H _Two NCO-Pyr (4) Me NH _Two O 2 1302 3-H _Two NCO-Pyr (4) Et NH _Two O 2 1303 3-H _Two NCO-Pyr (4) Pr NH _Two O 2 1304 3-H _Two NCO-Pyr (4) Pr ⁱ NH _Two O 2 1305 2-MeNHCO-Pyr (4) H NH _Two O 2 1306 2-MeNHCO-Pyr (4) Cl NH _Two O 2 1307 2-MeNHCO-Pyr (4) Me NH _Two O 2 1308 2-MeNHCO-Pyr (4) Et NH _Two O 2 1309 2-MeNHCO-Pyr (4) Pr NH _Two O 2 1310 2-MeNHCO-Pyr (4) Pr ⁱ NH _Two O 2 1311 3-MeNHCO-Pyr (4) H NH _Two O 2 1312 3-MeNHCO-Pyr (4) Cl NH _Two O 2 1313 3-MeNHCO-Pyr (4) Me NH _Two O 2 1314 3-MeNHCO-Pyr (4) Et NH _Two O 2 1315 3-MeNHCO-Pyr (4) Pr NH _Two O 2 1316 3-MeNHCO-Pyr (4) Pr ⁱ NH _Two O 2 1317 2- (Me) _Two NCO-Pyr (4) H NH _Two O 2 1318 2- (Me) _Two NCO-Pyr (4) Cl NH _Two O 2 1319 2- (Me) _Two NCO-Pyr (4) Me NH _Two O 2 1320 2- (Me) _Two NCO-Pyr (4) Et NH _Two O 2 1321 2- (Me) _Two NCO-Pyr (4) Pr NH _Two O 2 1322 2- (Me) _Two NCO-Pyr (4) Pr ⁱ NH _Two O 2 1323 3- (Me) _Two NCO-Pyr (4) H NH _Two O 2 1324 3- (Me) _Two NCO-Pyr (4) Cl NH _Two O 2 1325 3- (Me) _Two NCO-Pyr (4) Me NH _Two O 2 1326 3- (Me) _Two NCO-Pyr (4) Et NH _Two O 2 1327 3- (Me) _Two NCO-Pyr (4) Pr NH _Two O 2 1328 3- (Me) _Two NCO-Pyr (4) Pr ⁱ NH _Two O 2 1329 Pyrazinyl (2) H NH _Two O 2 1330 Pyrazinyl (2) Cl NH _Two O 2 1331 Pyrazinyl (2) Me NH _Two O 2 1332 Pyrazinyl (2) Et NH _Two O 2 1333 Pyrazinyl (2) Pr NH _Two O 2 1334 Pyrazinyl (2) Pr ⁱ NH _Two O 2 1335 Pyrimidinyl (2) H NH _Two O 2 1336 Pyrimidinyl (2) Cl NH _Two O 2 1337 Pyrimidinyl (2) Me NH _Two O 2 1338 Pyrimidinyl (2) Et NH _Two O 2 1339 Pyrimidinyl (2) Pr NH _Two O 2 1340 Pyrimidinyl (2) Pr ⁱ NH _Two O 2 1341 Pyridazinyl (3) H NH _Two O 2 1342 Pyridazinyl (3) Cl NH _Two O 2 1343 Pyridazinyl (3) Me NH _Two O 2 1344 Pyridazinyl (3) Et NH _Two O 2 1345 Pyridazinyl (3) Pr NH _Two O 2 1346 Pyridazinyl (3) Pr ⁱ NH _Two O 2 (Continuation of Table 1) Compound number R ¹ R ^Two R ^Three X n 1347 Ph H NHAc O 2 1348 Ph H NHMoc O 2 1349 Ph H NHBz O 2 1350 Ph H Pyrd (1) O 2 1351 Ph H Piz (1) O 2 1352 Ph Cl NHAc O 2 1353 Ph Cl NHMoc O 2 1354 Ph Cl NHBz O 2 1355 Ph Cl Pyrd (1) O 2 1356 Ph Cl Piz (1) O 2 1357 Ph Br NH _Two O 2 1358 Ph Br NH _Two S 2 1359 Ph I NH _Two O 2 1360 Ph I NH _Two S 2 1361 Ph Et NHAc O 2 1362 Ph Et NHMoc O 2 1363 Ph Et NHBz O 2 1364 Ph Et Pyrd (1) O 2 1365 Ph Et Piz (1) O 2 1366 Ph Pr NHAc O 2 1367 Ph Pr NHMoc O 2 1368 Ph Pr NHBz O 2 1369 Ph Pr Pyrd (1) O 2 1370 Ph Pr Piz (1) O 2 1371 Ph Pr ⁱ NHAc O 2 1372 Ph Pr ⁱ NHMoc O 2 1373 Ph Pr ⁱ NHBz O 2 1374 Ph Pr ⁱ Pyrd (1) O 2 1375 Ph Pr ⁱ Piz (1) O 2 1376 Ph Bu ⁱ NHAc O 2 1377 Ph Bu ⁱ NHMoc O 2 1378 Ph Bu ⁱ NHBz O 2 1379 Ph Bu ⁱ Pyrd (1) O 2 1380 Ph Bu ⁱ Piz (1) O 2 1381 Ph Bu ^t NHAc O 2 1382 Ph Bu ^t NHMoc O 2 1383 Ph Bu ^t NHBz O 2 1384 Ph Bu ^t Pyrd (1) O 2 1385 Ph Bu ^t Piz (1) O 2 1386 Ph Pn NH _Two O 2 1387 Ph Pn NH _Two S 2 1388 Ph Hex NH _Two O 2 1389 Ph Hex NH _Two S 2 1390 Ph 1-Cl-Et NH _Two O 2 1391 Ph 1-Cl-Et NH _Two S 2 1392 Ph All NH _Two O 2 1393 Ph All NH _Two S 2 1394 Ph Pre ⁱ NH _Two O 2 1395 Ph Pre ⁱ NH _Two S 2 1396 Ph Bun (2) NH _Two O 2 1397 Ph Bun (2) NH _Two S 2 1398 Ph Prg NH _Two O 2 1399 Ph Prg NH _Two S 2 1400 Ph Pr ^c NH _Two O 2 1401 Ph Pr ^c NH _Two S 2 1402 Ph Pn ^c NH _Two O 2 1403 Ph Pn ^c NH _Two S 2 1404 Ph Pen ^c (2) NH _Two O 2 1405 Ph Pen ^c (2) NH _Two S 2 1406 Ph CN NH _Two O 2 1407 Ph CN NH _Two S 2 1408 Ph COOH NH _Two O 2 1409 Ph COOH NH _Two S 2 1410 Ph Ac NH _Two O 2 1411 Ph Ac NH _Two S 2 1412 Ph COOMe NH _Two O 2 1413 Ph COOMe NH _Two S 2 1414 Ph CONH _Two NH _Two O 2 1415 Ph CONH _Two NH _Two S 2 1416 Ph CONHMe NH _Two O 2 1417 Ph CONHMe NH _Two S 2 1418 2,4-diF-Ph Br NH _Two O 2 1419 2,4-diF-Ph I NH _Two O 2 1420 2,4-diF-Ph Pn NH _Two O 2 1421 2,4-diF-Ph Hex NH _Two O 2 1422 2,4-diF-Ph 1-Cl-Et NH _Two O 2 1423 2,4-diF-Ph All NH _Two O 2 1424 2,4-diF-Ph Pre ⁱ NH _Two O 2 1425 2,4-diF-Ph Bun (2) NH _Two O 2 1426 2,4-diF-Ph Prg NH _Two O 2 1427 2,4-diF-Ph Pr ^c NH _Two O 2 1428 2,4-diF-Ph Pn ^c NH _Two O 2 1429 2,4-diF-Ph Pen ^c (2) NH _Two O 2 1430 2,4-diF-Ph CN NH _Two O 2 1431 2,4-diF-Ph COOH NH _Two O 2 1432 2,4-diF-Ph Ac NH _Two O 2 1433 2,4-diF-Ph COOMe NH _Two O 2 1434 2,4-diF-Ph CONH _Two NH _Two O 2 1435 2,4-diF-Ph CONHMe NH _Two O 2 1436 2,4-diF-Ph Br NH _Two S 2 1437 2,4-diF-Ph I NH _Two S 2 1438 2,4-diF-Ph Pn NH _Two S 2 1439 2,4-diF-Ph Hex NH _Two S 2 1440 2,4-diF-Ph 1-Cl-Et NH _Two S 2 1441 2,4-diF-Ph All NH _Two S 2 1442 2,4-diF-Ph Pre ⁱ NH _Two S 2 1443 2,4-diF-Ph Bun (2) NH _Two S 2 1444 2,4-diF-Ph Prg NH _Two S 2 1445 2,4-diF-Ph Pr ^c NH _Two S 2 1446 2,4-diF-Ph Pn ^c NH _Two S 2 1447 2,4-diF-Ph Pen ^c (2) NH _Two S 2 1448 2,4-diF-Ph CN NH _Two S 2 1449 2,4-diF-Ph COOH NH _Two S 2 1450 2,4-diF-Ph Ac NH _Two S 2 1451 2,4-diF-Ph COOMe NH _Two S 2 1452 2,4-diF-Ph CONH _Two NH _Two S 2 1453 2,4-diF-Ph CONHMe NH _Two S 2 1454 2-Cl-Ph Br NH _Two O 2 1455 2-Cl-Ph I NH _Two O 2 1456 2-Cl-Ph Pn NH _Two O 2 1457 2-Cl-Ph Hex NH _Two O 2 1458 2-Cl-Ph 1-Cl-Et NH _Two O 2 1459 2-Cl-Ph All NH _Two O 2 1460 2-Cl-Ph Bun (2) NH _Two O 2 1461 2-Cl-Ph Pre ⁱ NH _Two O 2 1462 2-Cl-Ph Prg NH _Two O 2 1463 2-Cl-Ph Pr ^c NH _Two O 2 1464 2-Cl-Ph Pn ^c NH _Two O 2 1465 2-Cl-Ph Pen ^c (2) NH _Two O 2 1466 2-Cl-Ph CN NH _Two O 2 1467 2-Cl-Ph COOH NH _Two O 2 1468 2-Cl-Ph Ac NH _Two O 2 1469 2-Cl-Ph COOMe NH _Two O 2 1470 2-Cl-Ph CONH _Two NH _Two O 2 1471 2-Cl-Ph CONHMe NH _Two O 2 1472 2-Cl-Ph Br NH _Two S 2 1473 2-Cl-Ph I NH _Two S 2 1474 2-Cl-Ph Pn NH _Two S 2 1475 2-Cl-Ph Hex NH _Two S 2 1476 2-Cl-Ph 1-Cl-Et NH _Two S 2 1477 2-Cl-Ph All NH _Two S 2 1478 2-Cl-Ph Bun (2) NH _Two S 2 1479 2-Cl-Ph Pre ⁱ NH _Two S 2 1480 2-Cl-Ph Prg NH _Two S 2 1481 2-Cl-Ph Pr ^c NH _Two S 2 1482 2-Cl-Ph Pn ^c NH _Two S 2 1483 2-Cl-Ph Pen ^c (2) NH _Two S 2 1484 2-Cl-Ph CN NH _Two S 2 1485 2-Cl-Ph COOH NH _Two S 2 1486 2-Cl-Ph Ac NH _Two S 2 1487 2-Cl-Ph COOMe NH _Two S 2 1488 2-Cl-Ph CONH _Two NH _Two S 2 1489 2-Cl-Ph CONHMe NH _Two S 2 1490 4-Cl-Ph Br NH _Two O 2 1491 4-Cl-Ph I NH _Two O 2 1492 4-Cl-Ph Pn NH _Two O 2 1493 4-Cl-Ph Hex NH _Two O 2 1494 4-Cl-Ph 1-Cl-Et NH _Two O 2 1495 4-Cl-Ph All NH _Two O 2 1496 4-Cl-Ph Bun (2) NH _Two O 2 1497 4-Cl-Ph Pre ⁱ NH _Two O 2 1498 4-Cl-Ph Prg NH _Two O 2 1499 4-Cl-Ph Pr ^c NH _Two O 2 1500 4-Cl-Ph Pn ^c NH _Two O 2 1501 4-Cl-Ph Pen ^c (2) NH _Two O 2 1502 4-Cl-Ph CN NH _Two O 2 1503 4-Cl-Ph COOH NH _Two O 2 1504 4-Cl-Ph Ac NH _Two O 2 1505 4-Cl-Ph COOMe NH _Two O 2 1506 4-Cl-Ph CONH _Two NH _Two O 2 1507 4-Cl-Ph CONHMe NH _Two O 2 1508 4-Cl-Ph Br NH _Two S 2 1509 4-Cl-Ph I NH _Two S 2 1510 4-Cl-Ph Pn NH _Two S 2 1511 4-Cl-Ph Hex NH _Two S 2 1512 4-Cl-Ph 1-Cl-Et NH _Two S 2 1513 4-Cl-Ph All NH _Two S 2 1514 4-Cl-Ph Bun (2) NH _Two S 2 1515 4-Cl-Ph Pre ⁱ NH _Two S 2 1516 4-Cl-Ph Prg NH _Two S 2 1517 4-Cl-Ph Pr ^c NH _Two S 2 1518 4-Cl-Ph Pn ^c NH _Two S 2 1519 4-Cl-Ph Pen ^c (2) NH _Two S 2 1520 4-Cl-Ph CN NH _Two S 2 1521 4-Cl-Ph COOH NH _Two S 2 1522 4-Cl-Ph Ac NH _Two S 2 1523 4-Cl-Ph COOMe NH _Two S 2 1524 4-Cl-Ph CONH _Two NH _Two S 2 1525 4-Cl-Ph CONHMe NH _Two S 2 1526 2,3-diCl-Ph H NH _Two O 2 1527 2,3-diCl-Ph Cl NH _Two O 2 1528 2,3-diCl-Ph Et NH _Two O 2 1529 2,3-diCl-Ph Pr NH _Two O 2 1530 2,3-diCl-Ph Pr ⁱ NH _Two O 2 1531 2,3-diCl-Ph Bu ⁱ NH _Two O 2 1532 2,3-diCl-Ph Bu ^t NH _Two O 2 1533 2,3-diCl-Ph H NH _Two S 2 1534 2,3-diCl-Ph Cl NH _Two S 2 1535 2,3-diCl-Ph Et NH _Two S 2 1536 2,3-diCl-Ph Pr NH _Two S 2 1537 2,3-diCl-Ph Pr ⁱ NH _Two S 2 1538 2,3-diCl-Ph Bu ⁱ NH _Two S 2 1539 2,3-diCl-Ph Bu ^t NH _Two S 2 1540 2,4-diCl-Ph Br NH _Two O 2 1541 2,4-diCl-Ph I NH _Two O 2 1542 2,4-diCl-Ph Pn NH _Two O 2 1543 2,4-diCl-Ph Hex NH _Two O 2 1544 2,4-diCl-Ph 1-Cl-Et NH _Two O 2 1545 2,4-diCl-Ph All NH _Two O 2 1546 2,4-diCl-Ph Bun (2) NH _Two O 2 1547 2,4-diCl-Ph Pre ⁱ NH _Two O 2 1548 2,4-diCl-Ph Prg NH _Two O 2 1549 2,4-diCl-Ph Pr ^c NH _Two O 2 1550 2,4-diCl-Ph Pn ^c NH _Two O 2 1551 2,4-diCl-Ph Pen ^c (2) NH _Two O 2 1552 2,4-diCl-Ph CN NH _Two O 2 1553 2,4-diCl-Ph COOH NH _Two O 2 1554 2,4-diCl-Ph Ac NH _Two O 2 1555 2,4-diCl-Ph COOMe NH _Two O 2 1556 2,4-diCl-Ph CONH _Two NH _Two O 2 1557 2,4-diCl-Ph CONHMe NH _Two O 2 1558 2,4-diCl-Ph Br NH _Two S 2 1559 2,4-diCl-Ph I NH _Two S 2 1560 2,4-diCl-Ph Pn NH _Two S 2 1561 2,4-diCl-Ph Hex NH _Two S 2 1562 2,4-diCl-Ph 1-Cl-Et NH _Two S 2 1563 2,4-diCl-Ph All NH _Two S 2 1564 2,4-diCl-Ph Bun (2) NH _Two S 2 1565 2,4-diCl-Ph Pre ⁱ NH _Two S 2 1566 2,4-diCl-Ph Prg NH _Two S 2 1567 2,4-diCl-Ph Pr ^c NH _Two S 2 1568 2,4-diCl-Ph Pn ^c NH _Two S 2 1569 2,4-diCl-Ph Pen ^c (2) NH _Two S 2 1570 2,4-diCl-Ph CN NH _Two S 2 1571 2,4-diCl-Ph COOH NH _Two S 2 1572 2,4-diCl-Ph Ac NH _Two S 2 1573 2,4-diCl-Ph COOMe NH _Two S 2 1574 2,4-diCl-Ph CONH _Two NH _Two S 2 1575 2,4-diCl-Ph CONHMe NH _Two S 2 1576 2,4-diCl-3-Me-Ph H NH _Two O 2 1577 2,4-diCl-3-Me-Ph Cl NH _Two O 2 1578 2,4-diCl-3-Me-Ph Et NH _Two O 2 1579 2,4-diCl-3-Me-Ph Pr NH _Two O 2 1580 2,4-diCl-3-Me-Ph Pr ⁱ NH _Two O 2 1581 2,4-diCl-3-Me-Ph Bu ⁱ NH _Two O 2 1582 2,4-diCl-3-Me-Ph Bu ^t NH _Two O 2 1583 2,4-diCl-3-Me-Ph H NH _Two S 2 1584 2,4-diCl-3-Me-Ph Cl NH _Two S 2 1585 2,4-diCl-3-Me-Ph Et NH _Two S 2 1586 2,4-diCl-3-Me-Ph Pr NH _Two S 2 1587 2,4-diCl-3-Me-Ph Pr ⁱ NH _Two S 2 1588 2,4-diCl-3-Me-Ph Bu ⁱ NH _Two S 2 1589 2,4-diCl-3-Me-Ph Bu ^t NH _Two S 2 1590 2,4-diCl-3-Et-Ph H NH _Two O 2 1591 2,4-diCl-3-Et-Ph Cl NH _Two O 2 1592 2,4-diCl-3-Et-Ph Et NH _Two O 2 1593 2,4-diCl-3-Et-Ph Pr NH _Two O 2 1594 2,4-diCl-3-Et-Ph Pr ⁱ NH _Two O 2 1595 2,4-diCl-3-Et-Ph Bu ⁱ NH _Two O 2 1596 2,4-diCl-3-Et-Ph Bu ^t NH _Two O 2 1597 2,4-diCl-3-Et-Ph H NH _Two S 2 1598 2,4-diCl-3-Et-Ph Cl NH _Two S 2 1599 2,4-diCl-3-Et-Ph Et NH _Two S 2 1600 2,4-diCl-3-Et-Ph Pr NH _Two S 2 1601 2,4-diCl-3-Et-Ph Pr ⁱ NH _Two S 2 1602 2,4-diCl-3-Et-Ph Bu ⁱ NH _Two S 2 1603 2,4-diCl-3-Et-Ph Bu ^t NH _Two S 2 1604 3,4-diCl-Ph H NH _Two O 2 1605 3,4-diCl-Ph Cl NH _Two O 2 1606 3,4-diCl-Ph Et NH _Two O 2 1607 3,4-diCl-Ph Pr NH _Two O 2 1608 3,4-diCl-Ph Pr ⁱ NH _Two O 2 1609 3,4-diCl-Ph Bu ⁱ NH _Two O 2 1610 3,4-diCl-Ph Bu ^t NH _Two O 2 1611 3,4-diCl-Ph H NH _Two S 2 1612 3,4-diCl-Ph Cl NH _Two S 2 1613 3,4-diCl-Ph Et NH _Two S 2 1614 3,4-diCl-Ph Pr NH _Two S 2 1615 3,4-diCl-Ph Pr ⁱ NH _Two S 2 1616 3,4-diCl-Ph Bu ⁱ NH _Two S 2 1617 3,4-diCl-Ph Bu ^t NH _Two S 2 1618 4-Pr ⁱ -Ph H NH _Two O 2 1619 4-Pr ⁱ -Ph Cl NH _Two O 2 1620 4-Pr ⁱ -Ph Et NH _Two O 2 1621 4-Pr ⁱ -Ph Pr NH _Two O 2 1622 4-Pr ⁱ -Ph Pr ⁱ NH _Two O 2 1623 4-Pr ⁱ -Ph Bu ⁱ NH _Two O 2 1624 4-Pr ⁱ -Ph Bu ^t NH _Two O 2 1625 4-Pr ⁱ -Ph H NH _Two S 2 1626 4-Pr ⁱ -Ph Cl NH _Two S 2 1627 4-Pr ⁱ -Ph Et NH _Two S 2 1628 4-Pr ⁱ -Ph Pr NH _Two S 2 1629 4-Pr ⁱ -Ph Pr ⁱ NH _Two S 2 1630 4-Pr ⁱ -Ph Bu ⁱ NH _Two S 2 1631 4-Pr ⁱ -Ph Bu ^t NH _Two S 2 1632 4-PhO-Ph H NH _Two O 2 1633 4-PhO-Ph Cl NH _Two O 2 1634 4-PhO-Ph Et NH _Two O 2 1635 4-PhO-Ph Pr NH _Two O 2 1636 4-PhO-Ph Pr ⁱ NH _Two O 2 1637 4-PhO-Ph Bu ⁱ NH _Two O 2 1638 4-PhO-Ph Bu ^t NH _Two O 2 1639 4-PhO-Ph H NH _Two S 2 1640 4-PhO-Ph Cl NH _Two S 2 1641 4-PhO-Ph Et NH _Two S 2 1642 4-PhO-Ph Pr NH _Two S 2 1643 4-PhO-Ph Pr ⁱ NH _Two S 2 1644 4-PhO-Ph Bu ⁱ NH _Two S 2 1645 4-PhO-Ph Bu ^t NH _Two S 2 1646 4-BnO-Ph H NH _Two O 2 1647 4-BnO-Ph Cl NH _Two O 2 1648 4-BnO-Ph Et NH _Two O 2 1649 4-BnO-Ph Pr NH _Two O 2 1650 4-BnO-Ph Pr ⁱ NH _Two O 2 1651 4-BnO-Ph Bu ⁱ NH _Two O 2 1652 4-BnO-Ph Bu ^t NH _Two O 2 1653 4-BnO-Ph H NH _Two S 2 1654 4-BnO-Ph Cl NH _Two S 2 1655 4-BnO-Ph Et NH _Two S 2 1656 4-BnO-Ph Pr NH _Two S 2 1657 4-BnO-Ph Pr ⁱ NH _Two S 2 1658 4-BnO-Ph Bu ⁱ NH _Two S 2 1659 4-BnO-Ph Bu ^t NH _Two S 2 1660 4-NO _Two -Ph H NH _Two O 2 1661 4-NO _Two -Ph Cl NH _Two O 2 1662 4-NO _Two -Ph Et NH _Two O 2 1663 4-NO _Two -Ph Pr NH _Two O 2 1664 4-NO _Two -Ph Pr ⁱ NH _Two O 2 1665 4-NO _Two -Ph Bu ⁱ NH _Two O 2 1666 4-NO _Two -Ph Bu ^t NH _Two O 2 1667 4-NO _Two -Ph H NH _Two S 2 1668 4-NO _Two -Ph Cl NH _Two S 2 1669 4-NO _Two -Ph Et NH _Two S 2 1670 4-NO _Two -Ph Pr NH _Two S 2 1671 4-NO _Two -Ph Pr ⁱ NH _Two S 2 1672 4-NO _Two -Ph Bu ⁱ NH _Two S 2 1673 4-NO _Two -Ph Bu ^t NH _Two S 2 1674 4-OH-Ph H NH _Two O 2 1675 4-OH-Ph Cl NH _Two O 2 1676 4-OH-Ph Et NH _Two O 2 1677 4-OH-Ph Pr NH _Two O 2 1678 4-OH-Ph Pr ⁱ NH _Two O 2 1679 4-OH-Ph Bu ⁱ NH _Two O
2 1680 4-OH-Ph Bu ^t NH _Two O 2 1681 4-OH-Ph H NH _Two S 2 1682 4-OH-Ph Cl NH _Two S 2 1683 4-OH-Ph Et NH _Two S 2 1684 4-OH-Ph Pr NH _Two S 2 1685 4-OH-Ph Pr ⁱ NH _Two S 2 1686 4-OH-Ph Bu ⁱ NH _Two S 2 1687 4-OH-Ph Bu ^t NH _Two S 2 1688 4-AcO-Ph H NH _Two O 2 1689 4-AcO-Ph Cl NH _Two O 2 1690 4-AcO-Ph Et NH _Two O 2 1691 4-AcO-Ph Pr NH _Two O 2 1692 4-AcO-Ph Pr ⁱ NH _Two O 2 1693 4-AcO-Ph Bu ⁱ NH _Two O 2 1694 4-AcO-Ph Bu ^t NH _Two O 2 1695 4-AcO-Ph H NH _Two S 2 1696 4-AcO-Ph Cl NH _Two S 2 1697 4-AcO-Ph Et NH _Two S 2 1698 4-AcO-Ph Pr NH _Two S 2 1699 4-AcO-Ph Pr ⁱ NH _Two S 2 1700 4-AcO-Ph Bu ⁱ NH _Two S 2 1701 4-AcO-Ph Bu ^t NH _Two S 2 1702 4-NH _Two -Ph H NH _Two O 2 1703 4-NH _Two -Ph Cl NH _Two O 2 1704 4-NH _Two -Ph Et NH _Two O 2 1705 4-NH _Two -Ph Pr NH _Two O 2 1706 4-NH _Two -Ph Pr ⁱ NH _Two O 2 1707 4-NH _Two -Ph Bu ⁱ NH _Two O 2 1708 4-NH _Two -Ph Bu ^t NH _Two O 2 1709 4-NH _Two -Ph H NH _Two S 2 1710 4-NH _Two -Ph Cl NH _Two S 2 1711 4-NH _Two -Ph Et NH _Two S 2 1712 4-NH _Two -Ph Pr NH _Two S 2 1713 4-NH _Two -Ph Pr ⁱ NH _Two S 2 1714 4-NH _Two -Ph Bu ⁱ NH _Two S 2 1715 4-NH _Two -Ph Bu ^t NH _Two S 2 1716 4-BzHN-Ph H NH _Two O 2 1717 4-BzHN-Ph Cl NH _Two O 2 1718 4-BzHN-Ph Et NH _Two O 2 1719 4-BzHN-Ph Pr NH _Two O 2 1720 4-BzHN-Ph Pr ⁱ NH _Two O 2 1721 4-BzHN-Ph Bu ⁱ NH _Two O 2 1722 4-BzHN-Ph Bu ^t NH _Two O 2 1723 4-BzHN-Ph H NH _Two S 2 1724 4-BzHN-Ph Cl NH _Two S 2 1725 4-BzHN-Ph Et NH _Two S 2 1726 4-BzHN-Ph Pr NH _Two S 2 1727 4-BzHN-Ph Pr ⁱ NH _Two S 2 1728 4-BzHN-Ph Bu ⁱ NH _Two S 2 1729 4-BzHN-Ph Bu ^t NH _Two S 2 1730 Fur (2) Br NH _Two O 2 1731 Fur (2) I NH _Two O 2 1732 Fur (2) Pn NH _Two O 2 1733 Fur (2) Hex NH _Two O 2 1734 Fur (2) 1-Cl-Et NH _Two O 2 1735 Fur (2) All NH _Two O 2 1736 Fur (2) Pre ⁱ NH _Two O 2 1737 Fur (2) Bun (2) NH _Two O 2 1738 Fur (2) Prg NH _Two O 2 1739 Fur (2) Pr ^c NH _Two O 2 1740 Fur (2) Pn ^c NH _Two O 2 1741 Fur (2) Pen ^c (2) NH _Two O 2 1742 Fur (2) CN NH _Two O 2 1743 Fur (2) COOH NH _Two O 2 1744 Fur (2) Ac NH _Two O 2 1745 Fur (2) COOMe NH _Two O 2 1746 Fur (2) CONH _Two NH _Two O 2 1747 Fur (2) CONHMe NH _Two O 2 1748 Fur (2) Br NH _Two S 2 1749 Fur (2) I NH _Two S 2 1750 Fur (2) Pn NH _Two S 2 1751 Fur (2) Hex NH _Two S 2 1752 Fur (2) 1-Cl-Et NH _Two S 2 1753 Fur (2) All NH _Two S 2 1754 Fur (2) Pre ⁱ NH _Two S 2 1755 Fur (2) Bun (2) NH _Two S 2 1756 Fur (2) Prg NH _Two S 2 1757 Fur (2) Pr ^c NH _Two S 2 1758 Fur (2) Pn ^c NH _Two S 2 1759 Fur (2) Pen ^c (2) NH _Two S 2 1760 Fur (2) CN NH _Two S 2 1761 Fur (2) COOH NH _Two S 2 1762 Fur (2) Ac NH _Two S 2 1763 Fur (2) COOMe NH _Two S 2 1764 Fur (2) CONH _Two NH _Two S 2 1765 Fur (2) CONHMe NH _Two S 2 1766 Thi (2) Br NH _Two O 2 1767 Thi (2) I NH _Two O 2 1768 Thi (2) Pn NH _Two O 2 1769 Thi (2) Hex NH _Two O 2 1770 Thi (2) 1-Cl-Et NH _Two O 2 1771 Thi (2) All NH _Two O 2 1772 Thi (2) Pre ⁱ NH _Two O 2 1773 Thi (2) Bun (2) NH _Two O 2 1774 Thi (2) Prg NH _Two O 2 1775 Thi (2) Pr ^c NH _Two O 2 1776 Thi (2) Pn ^c NH _Two O 2 1777 Thi (2) Pen ^c (2) NH _Two O 2 1778 Thi (2) CN NH _Two O 2 1779 Thi (2) COOH NH _Two O 2 1780 Thi (2) Ac NH _Two O 2 1781 Thi (2) COOMe NH _Two O 2 1782 Thi (2) CONH _Two NH _Two O 2 1783 Thi (2) CONHMe NH _Two O 2 1784 Thi (2) Br NH _Two S 2 1785 Thi (2) I NH _Two S 2 1786 Thi (2) Pn NH _Two S 2 1787 Thi (2) Hex NH _Two S 2 1788 Thi (2) 1-Cl-Et NH _Two S 2 1789 Thi (2) All NH _Two S 2 1790 Thi (2) Pre ⁱ NH _Two S 2 1791 Thi (2) Bun (2) NH _Two S 2 1792 Thi (2) Prg NH _Two S 2 1793 Thi (2) Pr ^c NH _Two S 2 1794 Thi (2) Pn ^c NH _Two S 2 1795 Thi (2) Pen ^c (2) NH _Two S 2 1796 Thi (2) CN NH _Two S 2 1797 Thi (2) COOH NH _Two S 2 1798 Thi (2) Ac NH _Two S 2 1799 Thi (2) COOMe NH _Two S 2 1800 Thi (2) CONH _Two NH _Two S 2 1801 Thi (2) CONHMe NH _Two S 2 1802 Ph 1-Cl-Pr NH _Two O 2 1803 Ph 1-Cl-Pr NH _Two S 2 1804 Ph 1-Cl-Bu ⁱ NH _Two O 2 1805 Ph 1-Cl-Bu ⁱ NH _Two S 2 1806 Ph 1-Cl-Pn ⁱ NH _Two O 2 1807 Ph 1-Cl-Pn ⁱ NH _Two S 2 1808 2,4-diMe-Ph H NH _Two O 2 1809 2,4-diMe-Ph Pr ⁱ NH _Two O 2 1810 3,5-diMe-Ph H NH _Two O 2 1811 3,5-diMe-Ph Pr ⁱ NH _Two O 2 The isoxazole derivative having the general formula (I) of the present invention
In this context, preferred compounds include 1, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 25,
27, 28, 29, 30, 32, 36, 48, 50, 5
4, 66, 70, 74, 93, 95, 99, 111, 1
12, 113, 114, 115, 116, 117, 12
5, 127, 131, 143, 146, 147, 14
8, 149, 150, 151, 152, 153, 15
4, 155, 170, 171, 172, 173, 17
4, 175, 176, 177, 178, 179, 18
0, 188, 190, 194, 206, 208, 21
2, 224, 226, 230, 242, 244, 24
8, 260, 262, 263, 264, 266, 27
8, 296, 298, 314, 316, 332, 33
4, 350, 357, 363, 368, 379, 38
6, 397, 408, 469, 475, 481, 50
5, 510, 511, 517, 523, 535, 53
8, 539, 540, 541, 542, 543, 54
4, 545, 546, 562, 568, 574, 58
0, 586, 592, 598, 604, 610, 61
6, 622, 628, 724, 728, 729, 73
0, 731, 732, 733, 752, 764, 77
6,788,794,800,806,812,81
8, 824, 1056, 1061, 1347, 134
8, 1349, 1350, 1351, 1357, 135
9, 1386, 1388, 1390, 1392, 139
4, 1396, 1398, 1400, 1402, 140
4, 1406, 1408, 1410, 1412, 141
4, 1416, 1459, 1495, 1499, 150
0, 1526, 1545, 1549, 1550, 157
6, 1590, 1604, 1618, 1632, 164
6, 1660, 1674, 1688, 1702, 171
6, 1809 or 1811.

Further preferred compounds include 1, 4, 5,
6, 7, 8, 9, 11, 13, 14, 15, 30, 3
2, 36, 48, 50, 54, 66, 70, 74, 9
3, 95, 99, 111, 113, 117, 125, 1,
27, 131, 143, 147, 149, 150, 15
1, 170, 172, 176, 188, 190, 19
4, 206, 208, 212, 224, 226, 23
0, 242, 244, 248, 260, 262, 26
3, 264, 266, 278, 296, 298, 31
4, 316, 332, 334, 350, 357, 36
3, 368, 379, 386, 397, 408, 46
9, 475, 481, 505, 510, 511, 51
7, 523, 535, 538, 539, 540, 54
1,542,543,544,545,546,56
2,568,574,580,586,592,59
8, 604, 610, 616, 622, 628, 72
4,728,729,730,731,732,73
3, 752, 764, 776, 788, 794, 80
0, 806, 812, 818, 824, 1056, 10
61, 1392, 1394, 1398, 1809 or 1
811.

Still more preferred compounds are 1,4,
5, 6, 7, 8, 9, 11, 13, 14, 15, 30,
48, 66, 74, 93, 111, 117, 125, 1
43, 149, 150, 151, 170, 176, 18
8, 206, 224, 242, 260, 296, 31
4, 332, 350, 368, 386, 408, 46
9, 475, 481, 505, 510, 511, 51
7, 523, 535, 538, 539, 543, 56
8, 586, 598, 604, 622, 724, 73
3, 1392, 1394 or 1398.

Particularly preferred compounds include 1, 4, 5,
6, 7, 8, 9, 11, 13, 66, 93, 111, 1
17, 125, 143, 149, 150, 151, 17
0, 176, 224, 260, 332, 386, 51
0, 535, 539, 543, 604, 1392, 13
94 or 1398.

The most preferred compound is exemplified compound number-1: 3- (2-aminoethoxy)
-5-phenylisoxazole, Exemplified Compound No.-5: 3- (2-aminoethoxy)
-4-chloro-5-phenylisoxazole, exemplified compound No. -7: 3- (2-aminoethoxy)
-4-ethyl-5-phenylisoxazole, Exemplified Compound No. -8: 3- (2-aminoethoxy)
-5-phenyl-4-propylisoxazole, Exemplified Compound No. -9: 3- (2-aminoethoxy)
-4-isopropyl-5-phenylisoxazole, Exemplified Compound No. -11: 3- (2-aminoethoxy) -4-isobutyl-5-phenylisoxazole, Exemplified Compound No.-117: 3- (2-amino) (Ethoxy) -5- (2-chlorophenyl) -4-isopropylisoxazole, exemplified compound No.-143: 3- (2-aminoethoxy) -5- (4-chlorophenyl) isoxazole, exemplified compound number-151: 3- (2-aminoethoxy) -5- (4-chlorophenyl) -4-isopropylisoxazole, Exemplified Compound No.-176: 3- (2-aminoethoxy) -5- (2,4-dichlorophenyl) -4-isopropyl Isoxazole, Exemplified Compound No.-510: 3- (2-aminoethoxy) -5- (2-furyl) -4- Sopropyl isoxazole, Exemplified compound number -535: 3- (2-aminoethoxy) -5- (2-thienyl) isoxazole, Exemplified compound number -539: 3- (2-Aminoethoxy) -4-chloro-5 -(2-thienyl) isoxazole, Exemplified Compound No. -543: 3- (2-aminoethoxy) -4-isopropyl-5- (2-thienyl) isoxazole, Exemplified Compound No.-1392: 4-allyl-3- (2
-Aminoethoxy) -5-phenylisoxazole.

[0045]

BEST MODE FOR CARRYING OUT THE INVENTION A method for producing the compound of the present invention will be described below.

[0046]

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[0047]

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[0048]

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In the above formula, R ¹ , R ² , R ³ , X and n
Have the same meanings as described above, R ³ _a is an amino group or a mono-C ₁ -C ₆ alkylamino group included in R ^3, respectively, protected amino groups, protected mono C
Besides being a _1- C ₆ alkylamino group, it has the same meaning as R ³ , Y represents a hydroxyl group or a leaving group, and Z represents a halogen atom.

The protecting group of the amino group or a mono C ₁ -C ₆ alkylamino group R ³ _a will generally be particularly limited, it can be used without as long as it is a group which is used as a protecting group of amino group, for example, , Formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, pentanoyl group,
Pivaloyl group, a valeryl group, an isovaleryl group or a C ₁ -C ₆ alkanoyl group such as hexanoyl groups; chloroacetyl group, dichloroacetyl group, trichloroacetyl group, trifluoroacetyl group, 3-fluoro-propionyl group, 4,4-dichloro Halogen or C ₁ such as butyryl, methoxyacetyl, butoxyacetyl, ethoxypropionyl or propoxybutyryl;
A C ₁ -C ₄ alkanoyl group substituted with —C ₄ alkoxy; an unsaturated C ₁ -C ₄ alkanoyl group such as an acryloyl group, a propioloyl group, a methacryloyl group, a crotonoyl group or an isocrotonoyl group;
α-naphthoyl group, β-naphthoyl group, 2-fluorobenzoyl group, 2-bromobenzoyl group, 2,4-dichlorobenzoyl group, 6-chloro-α-naphthoyl group, 4-
Toluoyl group, 4-propylbenzoyl group, 4-t-butylbenzoyl group, 2,4,6-trimethylbenzoyl group, 6-ethyl-α-naphthoyl group, 4-anisoyl group, 4-propoxybenzoyl group, 4-t -Butoxybenzoyl group, 6-ethoxy-α-naphthoyl group, 2-ethoxycarbonylbenzoyl group, 4-t-butoxycarbonylbenzoyl group, 6-methoxycarbonyl-α-naphthoyl group, 4-phenylbenzoyl group, 4-phenyl- α-naphthoyl group, 6-α-naphthylbenzoyl group,
Halogen, C such as 4-nitrobenzoyl group, 2-nitrobenzoyl group or 6-nitro-α-naphthoyl group;
₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄
Alkoxycarbonyl, C ₆ -C ₁₀ ants - may be substituted with Le or nitro, C ₆ -C ₁₀ Ari - nyl group; a methoxycarbonyl group, an ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group,
Butoxycarbonyl group, isobutoxycarbonyl group, s
-Butoxycarbonyl group, t-butoxycarbonyl group,
Chloromethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, 2-fluoropropoxycarbonyl group, 2-bromo-t-butoxycarbonyl group, 2,
Halogen such as 2-dibromo-t-butoxycarbonyl group, triethylsilylmethoxycarbonyl group, 2-trimethylsilylethoxycarbonyl group, 4-tripropylsilylbutoxycarbonyl group or t-butyldimethylsilylpropoxycarbonyl group or tri-C ₁ -C C ₁ -C ₄ alkoxycarbonyl group which may be substituted by ₄ alkylsilyl; C such as vinyloxycarbonyl group, allyloxycarbonyl group, 1,3-butadienyloxycarbonyl group or 2-pentenyloxycarbonyl group
₂ -C ₅ alkenyloxycarbonyl group; an aryl dicarbonyl groups, such as phthaloyl group; a benzyl group, phenethyl group, 3-phenylpropyl, 4-phenylbutyl group, alpha-naphthylmethyl group, beta-naphthylmethyl group, diphenyl An aralkyl group such as a methyl group, a triphenylmethyl group, an α-naphthyldiphenylmethyl group or a 9-anthrylmethyl group; or a benzyloxycarbonyl group;
(1-phenyl) benzyloxycarbonyl group, α-naphthylmethyloxycarbonyl group, β-naphthylmethyloxycarbonyl group, 9-anthrylmethyloxycarbonyl group, p-methoxybenzyloxycarbonyl group or p-nitrobenzyloxycarbonyl group And a C ₇ -C ₁₅ aralkyloxycarbonyl group which may be substituted by methoxy or nitro, and is preferably a C ₁ -C _15
4 alkanoyl group; a trifluoroacetyl group; methoxyacetyl group; a benzoyl group; alpha - naphthoyl groups; beta-naphthoyl group; anisoyl group; nitrobenzoyl group; C ₁
-C ₄ alkoxycarbonyl group; a methoxycarbonyl group; ethoxycarbonyl group; t-butoxycarbonyl group; 2,2,2-trichloroethoxycarbonyl group; triethylsilyl methoxycarbonyl group; 2-trimethylsilyl ethoxycarbonyl group; vinyl oxycarbonyl group; Allyloxycarbonyl group; phthaloyl group; benzyl group; benzyloxycarbonyl group; or nitrobenzyloxycarbonyl group, more preferably formyl group, acetyl group, benzoyl group, 4-anisoyl group,
-Nitrobenzoyl group, methoxycarbonyl group, ethoxycarbonyl group, butoxycarbonyl group, t-butoxycarbonyl group, phthaloyl group, benzyl group, benzyloxycarbonyl group or p-nitrobenzyloxycarbonyl group, particularly preferably t- Butoxycarbonyl group.

The leaving group for Y is not particularly limited as long as it is a group capable of leaving as a nucleophilic residue. Examples thereof include a halogen atom such as a chlorine atom, a bromine atom and an iodine atom; A C ₁ -C ₄ alkanesulfonyloxy group such as a group, an ethanesulfonyloxy group, a propanesulfonyloxy group or a butanesulfonyloxy group; a trifluoromethanesulfonyloxy group, a 2,2,2-trichloroethanesulfonyloxy group, 3, -tribromopropanesulfonyloxy group or 4,4,4
A halogeno C ₁ -C ₄ alkanesulfonyloxy group, such as a trifluorobutanesulfonyloxy group; or a benzenesulfonyloxy group, an α-naphthylsulfonyloxy group, a β-naphthylsulfonyloxy group, a p-toluenesulfonyloxy group, 4-t-butylbenzenesulfonyloxy group, mesitylenesulfonyloxy group or 6-
C, such as an ethyl-α-naphthylsulfonyloxy group
₁ -C ₄ alkyl with 1 to -C C ₆ which may have 3 ₁₀ Yes - Le sulfonyloxy group obtained, preferably a chlorine atom, a bromine atom, an iodine atom; a methanesulfonyloxy group,
An ethanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a 2,2,2-trichloroethanesulfonyloxy group; a benzenesulfonyloxy group, a toluenesulfonyloxy group or a mesitylenesulfonyloxy group, more preferably a chlorine atom, a bromine atom, Iodine atom,
A methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group or a mesitylenesulfonyloxy group.

The halogen atom for Z is, for example, a fluorine atom,
It may be a chlorine, bromine or iodine atom, preferably a chlorine atom.

Method A is a method for producing compound (I).

The step A1 is carried out in an inert solvent or in the absence of a solvent (preferably in an inert solvent), in the presence or absence of a base (preferably in the presence of a base), the compound (II) To produce a compound having the general formula (III). The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Or an aromatic hydrocarbon such as xylene; a halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or diethyl ether;
Ethers such as diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, preferably
Halogenated hydrocarbons (especially methylene chloride) or ethers (especially tetrahydrofuran or dioxane).

The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal hydrogen carbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; triethylamine, triethylamine. Butylamine, diisopropylethylamine, N-methylmorpholine, pyridine,
4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-
Diazabicyclo [4.3.0] non-5-ene (DB
N), 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.
0] It can be organic amines such as undec-7-ene (DBU), preferably alkali metal carbonates or organic amines, more preferably organic amines (especially triethylamine or pyridine). . The halogenating agent used is, for example, phosphorus oxychloride, phosphorus oxybromide,
It may be phosphorus oxyiodide or phosphorus pentachloride or a mixture thereof, preferably phosphorus oxychloride, phosphorus pentachloride or a mixture thereof.

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually 0 ° C. to 150 ° C., preferably 10 ° C.
C. to 100.degree.

The reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually from 30 minutes to 10 hours, preferably from 1 hour to 5 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, the solvent is distilled off, water is poured into the reaction solution, a water-immiscible solvent (for example, benzene, ether, ethyl acetate, etc.) is added and extracted, the organic layer is washed with water, dried over anhydrous magnesium sulfate, etc. Is distilled off to obtain the desired compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Step A2 is a step of reacting compound (III) with a compound having the general formula (IV) in an inert solvent in the presence of a base to produce a compound having the general formula (V).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; formamide, dimethylformamide;
Amides, such as dimethylacetamide or hexamethylphosphoric triamide; or sulfoxides, such as dimethylsulfoxide or sulfolane, preferably
Ethers, amides or sulfoxides, more preferably ethers (particularly diethyl ether, tetrahydrofuran or dioxane) or amides (particularly dimethylformamide).

The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal hydrogen carbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; lithium hydride Alkali metal hydrides such as sodium hydroxide or potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine , Pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nona-5
-Ene (DBN), 1,4-diazabicyclo [2.2.
2] organic amines such as octane (DABCO) or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU); alkyllithiums such as methyllithium, ethyllithium or butyllithium; Can be lithium alkylamides such as lithium diisopropylamide or lithium dicyclohexylamide, preferably alkali metal carbonates, alkali metal hydrides or organic amines, more preferably alkali metal carbonates (Especially sodium carbonate or potassium carbonate) or alkali metal hydrides (especially sodium hydride).

Incidentally, crown ethers such as dibenzo-18-crown-6 may be added to make the reaction proceed effectively.

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -10 ° C to 150 ° C, preferably from 0 ° C to 80 ° C.

The reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually from 30 minutes to 30 hours, preferably from 1 hour to 10 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, the reaction solution is appropriately neutralized, and if there is any insoluble matter, it is filtered off if necessary. , Ethyl acetate, etc.)
After extraction and washing with water, the organic layer containing the target compound is dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The step A3 is a step for producing a compound (I) by removing a protecting group for an amino group or an alkylamino group, if desired.

The removal of the protecting group for the amino group varies depending on its type, but is generally carried out as follows by a method well known in the art of organic synthetic chemistry.

[0068] amino-protecting group is, C ₁ -C ₆ alkanoyl group (preferably formyl or acetyl); C ₆ -
A C ₁₀ arylcarbonyl group (preferably a benzoyl group);
It may be substituted by halogen or tri C ₁ -C ₄ alkylsilyl, C ₁ -C ₄ alkoxycarbonyl group (preferably a methoxycarbonyl group, an ethoxycarbonyl group, t-
Butoxycarbonyl group, 2-trimethylsilylethoxycarbonyl group, 2-bromo-t-butoxycarbonyl group or 2,2-dibromo-t-butoxycarbonyl group);
A C ₂ -C ₅ alkenyloxycarbonyl group (preferably a vinyloxycarbonyl group); or a C ₇ -C ₁₅ aralkyloxycarbonyl group which may be substituted by methoxy or nitro (preferably a benzyloxycarbonyl group, (1 -Phenyl) benzyloxycarbonyl group, 9-anthrylmethyloxycarbonyl group, p-methoxybenzyloxycarbonyl group or p-nitrobenzyloxycarbonyl group), when the acid is used in an inert solvent or an aqueous solvent. It can be removed by processing. In this case, the target compound can be obtained as a salt. The acid used can be, for example, an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid or trifluoroacetic acid.
Hydrochloric acid, sulfuric acid, hydrobromic acid or trifluoroacetic acid.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; esters such as methyl acetate or ethyl acetate; methanol, ethanol, propanol Alcohols, such as isopropanol or butanol; amides, such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; sulfoxides, such as dimethylsulfoxide or sulfolane; fatty acids, such as formic acid or acetic acid; The solvent may be water or a mixed solvent of water and the above-mentioned solvent, preferably a halogenated hydrocarbon, ether, alcohol, fatty acid or water and the above-mentioned solvent. A mixed solvent of, even more preferably halogenated hydrocarbons (particularly methylene chloride), ethers (particularly tetrahydrofuran or dioxane),
Fatty acids (especially acetic acid) or water or a mixed solvent of water and the above solvent.

The reaction temperature varies depending on the starting compound, solvent or acid used, but is usually from -10 ° C to 150 ° C, preferably from 0 ° C to 60 ° C.

The reaction time varies depending on the starting compound, solvent or acid used, but is usually 5 minutes to 20 hours, preferably 10 minutes to 5 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, the target compound precipitated in the reaction solution is collected by filtration, or the reaction solution is appropriately neutralized, the solvent is distilled off, water is poured into the reaction solution, and a water-immiscible solvent (eg, benzene, ether, acetic acid) Ethyl and the like are extracted, the organic layer containing the target compound is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

When the amino-protecting group is an alkanoyl, an arylcarbonyl, an alkoxycarbonyl, an alkenyloxycarbonyl, an aryldicarbonyl, an aralkyl or an aralkyloxycarbonyl, in an inert solvent or an aqueous solvent Can be removed by treating with a base.

The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate;
Alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; sodium hydroxide,
Alkali metal hydroxides such as potassium hydroxide or lithium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; such as sodium methyl mercaptan or sodium ethyl mercaptan Alkali metal salts, preferably alkali metal carbonates (particularly sodium or potassium carbonate), alkali metal hydroxides (particularly sodium hydroxide or potassium hydroxide), alkali metal alkoxides (particularly sodium methoxide). , Sodium ethoxide or potassium tert-butoxide) or organic amines (especially hydrazine or methylamine).

The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, propanol, isopropanol or butanol; Amides such as dimethylacetamide or hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide or sulfolane; or a mixed solvent of water and the above solvent,
Preferred are halogenated hydrocarbons, ethers, alcohols, or a mixed solvent of water and the above solvent, more preferably ethers (particularly tetrahydrofuran or dioxane), alcohols (particularly methanol, ethanol), Alternatively, it is a mixed solvent of water and the above solvent.

The reaction temperature varies depending on the starting compound, solvent or base used, but is usually from -10 ° C to 150 ° C.
And preferably from 0 ° C to 50 ° C.

The reaction time varies depending on the starting compound, solvent or base used, but is usually 30 minutes to 20 hours, preferably 1 hour to 5 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, the target compound precipitated in the reaction solution is collected by filtration or the solvent is distilled off,
Water is poured into the reaction solution, and the precipitate is collected by filtration, or a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added and extracted, and the organic layer containing the target compound is washed with water,
The target compound can be obtained by drying over anhydrous magnesium sulfate or the like and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

When the amino-protecting group is a tertiary-butoxycarbonyl group, it can also be removed by treating with a silyl compound or an acid in an inert solvent.

The silyl compound used can be, for example, trimethylsilyl chloride, trimethylsilyl iodide or trimethylsilyl trifluoromethanesulfonate, and the acid used is, for example, aluminum chloride,
Hydrochloric acid or trifluoroacetic acid.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; Ethers such as diethyl ether, tetrahydrofuran or dioxane; nitriles such as acetonitrile, preferably halogenated hydrocarbons (particularly methylene chloride, chloroform) or nitriles (particularly acetonitrile). .

The reaction temperature varies depending on the starting compound, reagent or solvent, but is usually from -20 ° C to 100 ° C.
Preferably it is 0 ° C to 50 ° C.

The reaction time varies depending on the starting compound, reagent, solvent, reaction temperature and the like, but is usually 10 minutes to 10 hours, preferably 30 minutes to 3 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, the solvent is distilled off, or the precipitated target compound is collected by filtration, or water is poured into the reaction solution, the aqueous layer is made alkaline, and the precipitate is collected by filtration,
Or a solvent immiscible with water (eg, benzene, ether,
Ethyl acetate) is added, and the mixture is extracted. The organic layer containing the target compound is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

When the protecting group of the amino group is an allyloxycarbonyl group, a solvent similar to that used in the removal method by catalytic reduction reaction of an aralkyl group or the like using palladium and triphenylphosphine or nickel tetracarbonyl. , Reaction temperature, reaction time and the like.

When the protecting group for the amino group is an aralkyl group or C
If it is ₇ -C ₁₁ aralkyloxycarbonyl group is usually performed in an inert solvent, contacting with a reducing agent (preferably,
The protecting group can be suitably removed by a method of removing the protective group by catalytic reduction in the presence of a catalyst) or a method of removing the protective group using an oxidizing agent. In the case of the reaction for removing the protecting group by catalytic reduction, the solvent to be used is not particularly limited as long as it does not participate in the reaction. For example, aliphatic hydrocarbons such as hexane or cyclohexane; toluene, benzene Or an aromatic hydrocarbon such as xylene; an ether such as diethyl ether, tetrahydrofuran or dioxane; an ester such as ethyl acetate or propyl acetate; such as methanol, ethanol or isopropanol. Alcohols; fatty acids such as formic acid or acetic acid; or a mixed solvent of these organic solvents and water, preferably aliphatic hydrocarbons, aromatic hydrocarbons, and ethers. , Esters, alcohols, fatty acids, or a mixed solvent of these organic solvents with water, and more preferably alcohols (particularly methanol or alcohol). Ethanol - Le), fatty acids (particularly formic acid or acetic acid), or a mixed solvent of these organic solvents and water.

The catalyst to be used is not particularly limited as long as it is used in a usual catalytic reduction reaction.
It can be palladium black, palladium-carbon, Raney-nickel, rhodium-aluminum oxide or palladium-barium sulfate, preferably palladium-carbon or Raney-nickel.

The pressure of hydrogen is not particularly limited, but is usually 1
To 10 atm, preferably 1 atm.

The reaction temperature varies depending on the starting compound, the solvent, the reducing agent used and the like, but is usually from 0 ° C. to 100 ° C.
And preferably 10 ° C to 50 ° C.

The reaction time varies depending on the starting compound, the solvent, the reducing agent used, the reaction temperature and the like, but is usually 15 minutes to 10 hours, preferably 30 minutes to 3 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after removing the catalyst by filtration, the solvent is distilled off, water is poured into the reaction solution, and the aqueous layer is made alkaline. ), And the mixture is extracted. The organic layer containing the target compound is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The solvent used in the removal method by oxidation is not particularly limited as long as it does not participate in the present reaction. Examples thereof include ketones such as acetone; and halogens such as methylene chloride, chloroform and carbon tetrachloride. Hydrocarbons; nitriles such as acetonitrile; ethers such as diethyl ether, tetrahydrofuran or dioxane; amides such as dimethylformamide, dimethylacetamide or hexamethylphosphorotriamide; sulfoxides such as dimethylsulfoxide. Or a mixed solvent of these organic solvents and water;
Preferably, ketones, halogenated hydrocarbons, nitriles, ethers, amides, sulfoxides, or a mixed solvent of these organic solvents and water, more preferably,
Ketones (especially acetone), halogenated hydrocarbons (especially methylene chloride), nitriles (especially acetonitrile), amides (especially hexamethylphosphorotriamide), sulfoxides (especially dimethylsulfoxide), or an organic solvent thereof and water And a mixed solvent.

The oxidizing agent used can be, for example, potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN) or 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), Preferably, it is ammonium cerium nitrate (CAN) or 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ).

The reaction temperature varies depending on the starting compound, the solvent, the oxidizing agent used and the like, but is usually from 0 ° C. to 150 ° C.
And preferably 10 ° C to 50 ° C.

The reaction time varies depending on the compound, solvent or oxidizing agent used, but is usually 15 minutes to 24 hours, preferably 30 minutes to 5 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, the solvent is distilled off after filtering off the oxidizing agent, water is poured into the reaction solution, the aqueous layer is made alkaline, and the precipitate is collected by filtration, or a solvent immiscible with water (eg, benzene, ether, ethyl acetate) And the like, and the mixture is extracted. The organic layer containing the target compound is washed with water, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

When the protecting group for the amino group is removed with an acid, the desired compound is usually obtained in the form of a salt.
Generally, the amino group of the target compound can be made a free base by removing the acid used by a method well known in the art of organic chemistry.

Method B is a method for separately producing compound (Va) in which X is an oxygen atom in intermediate (V) of method A.

Step B1 comprises the step of reacting the compound (II) with a compound of the formula (I)
This is a step of reacting a compound having Va) to produce a compound (Va).

When Y is a hydroxyl group, basically, Bulltin Chemical Society Japan, Vol.
2380 (1967) [ Bull. Chem. Soc. Jap. , 40 , 23]
80 (1967).] In the presence of a phosphine and an azo compound in an inert solvent according to the Mitsunobu reaction described in
The reaction is carried out by subjecting I) to a dehydration condensation reaction with the corresponding compound (IVa).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; , Toluene or xylene; aromatic hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxy Ethers such as ethane or diethylene glycol dimethyl ether, preferably aliphatic hydrocarbons,
Aromatic hydrocarbons or ethers, more preferably ethers (particularly diethyl ether or tetrahydrofuran).

[0102] phosphines used are, for example, trimethylphosphine, triethylphosphine, tripropylphosphine, tributylphosphine, tri C ₁ -C such tripentyl phosphine or trihexylphosphine
₆ alkyl phosphines; tri-C ₆ -C ₁₀ aryl phosphines such as triphenyl phosphine, triindenyl phosphine or trinaphthyl phosphine; or tolyl diphenyl phosphine, tolyl phosphine, trimesityl phosphine, tributyl phenyl phosphine or tri-
C ₁ -C ₄ , such as 6-ethyl-2-naphthylphosphine;
It may be a tri-C ₆ -C ₁₀ arylphosphine optionally having alkyl as a substituent, preferably a tri-C ₁ -C ₆ alkylphosphine (especially trimethylphosphine, triethylphosphine, tripropylphosphine or tributylphosphine) or tri C ₆ -C ₁₀ arylphosphine (particularly triphenylphosphine, tri indenyl phosphine or trinaphthylphosphine), and more preferably a tri-C ₆ -C ₁₀ arylphosphine (particularly triphenylphosphine).

The azo compound to be used is not particularly limited as long as it is a known azodicarboxylic acid derivative. Examples thereof include dimethyl azodicarboxylate, diethyl azodicarboxylate,
Be a azodicarboxylate dipropyl or azodicarboxylate di -C ₁ -C ₄ alkyl such as azodicarboxylate dibutyl preferably a azodicarboxylic acid dimethyl or diethyl azodicarboxylate.

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -10 ° C to 100 ° C, preferably from 0 ° C to 50 ° C.

The reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually 15 minutes to 48 hours, preferably 30 minutes to 24 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, if any insolubles are present, they are filtered off and the solvent is distilled off.
Alternatively, water is poured into the residue obtained by distilling off the solvent, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added to the residue, followed by extraction, washing with water, drying over anhydrous magnesium sulfate, etc., and distilling off the solvent. Yields the desired compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

When Y is a leaving group, compound (IVa) corresponding to compound (II) in an inert solvent in the presence of a base
To give compound (Va).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; formamide, dimethylformamide;
Amides, such as dimethylacetamide or hexamethylphosphoric triamide; or sulfoxides, such as dimethylsulfoxide or sulfolane, preferably
Amides or sulfoxides, more preferably amides (particularly dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide).

The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate;
Alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; sodium hydroxide,
Alkali metal hydroxides such as potassium hydroxide or lithium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; sodium methyl mercaptan or sodium ethyl mercaptan Alkali metals such as mercaptans; triethylamine, tributylamine, diisopropylethylamine,
N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline,
N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8
Organic amines such as diazabicyclo [5.4.0] undec-7-ene (DBU); alkyllithiums such as methyllithium, ethyllithium or butyllithium; lithium such as lithium diisopropylamide or lithium dicyclohexylamide. Alkylamides, preferably alkali metal carbonates, alkali metal hydrides or alkali metal hydroxides,
More preferred are alkali metal hydrides (particularly sodium hydroxide).

Incidentally, crown ethers such as dibenzo-18-crown-6 can also be added in order to carry out the reaction effectively.

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -10 ° C to 100 ° C, preferably from 0 ° C to 50 ° C.

The reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually 30 minutes to 20 hours, preferably 1 hour to 5 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, the reaction solution is appropriately neutralized, and if there is any insoluble matter, it is filtered off. The solvent is distilled off. And the like, and the mixture is extracted. The organic layer containing the target compound is washed with water, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the target compound. The resulting target compound is, if necessary,
It can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Method C is a method for separately producing compound (I) in Method A.

Step C1 is an optional step. Reaction (a): a reaction for introducing an alkyl group, an alkoxy group or a carboxy group into an isoxazole ring or an aromatic ring contained in R ¹ , reaction (b): A reaction for introducing a hydroxyalkyl group into an isoxazole ring or an aromatic ring contained in R ¹ , a reaction (c): a reaction for converting a hydroxy group contained in a hydroxyalkyl group generated by the reaction (b) into a halogen atom, a reaction ( d): a reaction of 1,2-elimination (β-elimination) of a hydroxy group contained in the hydroxyalkyl group generated by the reaction (b); Reaction (e): carbonyl conversion of the hydroxyalkyl group generated by the reaction (b) Reaction (f): reaction of esterifying a carboxy group, reaction (g): conversion of an alkoxycarbonyl group to a carbamoyl group Reaction (h): reaction for converting a carboxy group to a carbamoyl group, reaction (i): reaction for converting a carbamoyl group to a cyano group, reaction (j): conversion of an alkoxy group on an aromatic ring to a hydroxyl group Reaction, reaction (k): reaction for acylating a hydroxyl group or an amino group, reaction (l): reaction for aralkylating a hydroxyl group or an amino group, reaction (m): reaction for converting a nitro group to an amino group, and reaction ( n): comprising the reaction of removing the protecting group of the amino group contained in R ³ a, etc., it is performed by changing the appropriate order.

Reaction (a): The reaction for introducing an alkyl group, an alkoxy group or a carboxy group into the isoxazole ring or the aromatic ring contained in R ¹ in the reaction (a) is carried out by a method well known in organic synthetic chemistry. Will be For example, halogeno C ₁ -C ₆ alkane, di C
₁ -C ₆ (preferably in halogeno C ₁ -C ₆ alkane or carbon dioxide) alkyl carbonate or gas carbonate is carried out by reacting the.

The halogeno C ₁ -C ₆ alkanes used are, for example, methyl chloride, methyl bromide, methyl iodide, ethyl chloride, ethyl iodide, propyl bromide, butyl iodide, pentyl iodide or hexyl iodide. It can be, preferably methyl bromide or methyl iodide, more preferably methyl iodide.

The di-C ₁ -C ₆ alkyl carbonate used is, for example, dimethyl carbonate, diethyl carbonate, dipropyl carbonate, diisopropyl carbonate, dibutyl carbonate, dis-secondary butyl carbonate, di-tert-butyl carbonate,
It can be dipentyl carbonate or dihexyl carbonate, preferably dimethyl carbonate or diethyl carbonate.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; such as N, N, N ', N'-tetramethylethylenediamine Diamines; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide or hexamethylphosphorous triamide; or sulfoxides such as dimethylsulfoxide or sulfolane;
Ethers, amides or sulfoxides, more preferably ethers (particularly tetrahydrofuran).

The base used is, for example, an alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride; an alkyl lithium such as methyl lithium, ethyl lithium, butyl lithium or secondary butyl lithium; It may be a lithium alkyl amide such as lithium diisopropylamide, lithium dicyclohexylamide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide or sodium bis (trimethylsilyl) amide, preferably an alkyl lithium (particularly butyl lithium ) Or lithium alkylamides (particularly lithium diisopropylamide).

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -100 ° C to 30 ° C, preferably from -70 ° C to 0 ° C. The reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually 5 minutes to 10 hours, preferably 10 minutes to 5 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent is distilled off, if necessary, the aqueous layer is made acidic, and then a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) To extract the target compound. The extracted organic layer is washed with water, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Reaction (b): The reaction for introducing a hydroxyalkyl group into the isoxazole ring or the aromatic ring contained in R ¹ in the reaction (b) is performed by a method well known in organic synthetic chemistry. For example, the reaction is carried out by reacting with an aldehyde or a ketone in an inert solvent in the presence of a base.

The aldehydes can be, for example, straight-chain or branched-chain alkanals having 2 to 6 carbon atoms such as acetaldehyde, propionaldehyde, butyraldehyde, isobutyraldehyde, valeraldehyde, isovaleraldehyde or hexaaldehyde. , Preferably C _2-
C ₄ alkanal, more preferably acetaldehyde.

Ketones include, for example, acetone, 2-butanone, 2-pentanone, 3-pentanone, 3-methyl-2
A straight or branched chain having 3 to 6 carbon atoms such as butanone, 2-hexanone, 3-hexanone, 3-methyl-2-pentanone, 4-methyl-2-pentanone or 3,3-dimethyl-2-butanone. It may be a branched alkanone, preferably acetone, 2-butanone or 3-butanone, more preferably acetone.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; such as N, N, N ', N'-tetramethylethylenediamine Diamines; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide or hexamethylphosphorous triamide; or sulfoxides such as dimethylsulfoxide or sulfolane;
Ethers, amides or sulfoxides, more preferably ethers (particularly tetrahydrofuran).

The base used is, for example, an alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride; an alkyl lithium such as methyl lithium, ethyl lithium, butyl lithium or secondary butyl lithium; It may be a lithium alkyl amide such as lithium diisopropylamide, lithium dicyclohexylamide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide or sodium bis (trimethylsilyl) amide, preferably an alkyl lithium (particularly butyl lithium ) Or lithium alkylamides (particularly lithium diisopropylamide).

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -100 ° C to 30 ° C, preferably from -70 ° C to 0 ° C. The reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually 5 minutes to 10 hours, preferably 10 minutes to 5 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent has been distilled off, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extraction is performed. After washing the organic layer
The target compound can be obtained by drying over anhydrous magnesium sulfate or the like and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography. Reaction (c): The reaction of converting the hydroxy group contained in the hydroxyalkyl group generated by the reaction (b) into a halogen atom in the reaction (c) is performed by a method well-known in synthetic organic chemistry. For example, the reaction is performed by reacting with a hydrohalic acid in an inert solvent.

The hydrohalic acid used is, for example,
It can be hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid, preferably hydrochloric acid.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; esters such as methyl acetate or ethyl acetate; or water or water And a mixed solvent of the above solvent, and preferably a mixed solvent of ethers (particularly dioxane) or ethers and water. The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -50 ° C to 80 ° C.
° C, preferably 0 ° C to 50 ° C. The reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually 5 minutes to 10 hours, preferably 10 minutes to 5 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or water is poured into a residue obtained by distilling the solvent,
A solvent that is immiscible with water (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, the extracted organic layer is washed with water, dried over anhydrous magnesium sulfate, etc. can get. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Reaction (d): In the reaction (d), the reaction for 1,2-elimination (β-elimination) of the hydroxy group contained in the hydroxyalkyl group produced by the reaction (b) is as follows:
It is performed by a method well-known in organic synthetic chemistry. For example, the reaction is performed by reacting with an acid in an inert solvent.

The acids used are, for example, mineral acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; methanesulfonic acid, trifluoromethanesulfone A sulfonic acid such as an acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid;
Alternatively, it can be a carboxylic acid such as trifluoroacetic acid, fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid or maleic acid, preferably a mineral acid (particularly hydrochloric acid).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; or esters such as methyl acetate or ethyl acetate; Preferred are ethers or esters, and more preferred are ethers (particularly dioxane). The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually 0 ° C to 150 ° C, preferably 50 ° C.
C. to 130.degree. The reaction time depends on the starting compound, reagent,
Although it varies depending on the reaction temperature, it is usually 5 minutes to 10 hours, preferably 10 minutes to 5 hours. After the reaction,
The target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent has been distilled off, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extraction is performed. The obtained organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the desired compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Reaction (e): In the reaction (e), the reaction of converting the hydroxyalkyl group generated by the reaction (b) into a carbonyl group is performed by a method well known in synthetic organic chemistry. For example, the reaction is performed by reacting with an oxidizing agent in an inert solvent.

The oxidizing agent to be used is not particularly limited as long as it is usually used for an oxidation reaction. Examples thereof include manganese oxides such as potassium permanganate and manganese dioxide; and manganese oxides such as ruthenium tetroxide. Ruthenium oxides; silver compounds such as silver oxide; potassium chromate, chromate-
Inorganic metal oxidizing agents such as sulfuric acid complex, chromic acid compound such as chromic acid-pyridine complex, and cerium compound such as ammonium cerium nitrate (CAN); reagents used for DMSO oxidation (dimethyl sulfoxide and dicyclohexylcarbodiimide; A complex with zalyl chloride, acetic anhydride or phosphorus pentoxide or a pyridine-sulfuric anhydride complex); succinimides such as N-bromosuccinimide; or 2,3-dichloro-5,6-dicyano-p -An organic oxidizing agent such as a quinone compound such as benzoquinone (DDQ), preferably an inorganic metal oxidizing agent or D
Reagents used for MSO oxidation, more preferably inorganic metal oxidizing agents (especially chromic acid-pyridine complex).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone; esters such as methyl acetate or ethyl acetate Nitriles such as acetonitrile; amides such as dimethylformamide, dimethylacetamide or hexamethylphosphorotriamide; sulfoxides such as dimethylsulfoxide; or a mixed solvent of these organic solvents and water, Are halogenated hydrocarbons, ethers, ketones, nitriles, amides or sulfoxides, more preferably halogenated hydrocarbons (particularly methylene chloride).

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually 0 ° C. to 100 ° C., preferably 20 ° C.
C. to 50.degree. The reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually 30 minutes to 48 hours, preferably 1 hour to 30 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after filtering off the oxidizing agent, the solvent is distilled off, or water is poured into the residue from which the solvent is distilled off, and a water-immiscible solvent (for example, benzene, ether, ethyl acetate, etc.) is added to give the target compound. After extraction, the extracted organic layer is washed with water, dried over anhydrous magnesium sulfate or the like, and the target compound is obtained by distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Reaction (f): The reaction for esterifying a carboxy group in the reaction (f) is performed by a method well known in organic synthetic chemistry. For example, (1) reacting with an esterifying agent in an inert solvent, or (2) reacting with an active esterifying agent in an inert solvent to produce an active ester, and then reacting with an alcohol in the inert solvent. Or
(3) The reaction is carried out by reacting with a halogenating agent in an inert solvent to produce an acid halide and then reacting with an alcohol in an inert solvent. The esterifying agent used in the reaction (f1) is not particularly limited as long as it is generally used in the art of synthetic organic chemistry, and may be, for example, a diazoalkane or a trialkylsilyldiazoalkane. preferably, diazomethane, diazoethane, diazo propane, Jiazobutan, be a C ₁ -C ₆ diazoalkane or trimethylsilyldiazomethane, such as diazo pentane or diazo hexane, more preferably C ₁
—C ₄ diazoalkane or trimethylsilyldiazomethane, particularly preferably diazomethane.

The solvent used in the reaction using the diazo C ₁ -C ₆ alkane is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Aliphatic hydrocarbons such as, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride;
Halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; such as methyl acetate or ethyl acetate Esters;
Or a mixed solvent of the above solvents, preferably a halogenated hydrocarbon, an ether, an ester or a mixed solvent of the above solvents, and more preferably an ether (particularly diethyl ether), an ester (particularly acetic acid) Ethyl) or a mixed solvent of the above solvents.

The solvent used in the reaction using trimethylsilyldiazomethane is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, methanol, ethanol, propanol, isopropanol, Alcohols such as butanol, isobutanol, t-butanol, pentanol or hexanol;
Aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Selected from the group consisting of halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; and esters such as methyl acetate or ethyl acetate. And a mixture of alcohols (especially methanol) or aromatic hydrocarbons (especially benzene) and alcohols (especially methanol). Solvent.

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -10 ° C to 100 ° C, preferably from 10 ° C to 50 ° C. The reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually from 10 minutes to 10 minutes.
Time, preferably 15 minutes to 2 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, the target compound is obtained by distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The active esterifying agent used in the reaction (f2) is not particularly limited as long as it is generally used in the art of synthetic organic chemistry. Examples thereof include ethyl chloroformate and N-hydroxy The active esterification reaction may be an N-hydroxy compound such as succinimide, 1-hydroxybenzotriazole or N-hydroxy-5-norbornene-2,3-dicarboximide or a disulfide compound such as dipyridyl disulfide. It is preferably carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or triphenylphosphine. The solvent used in both reactions is
There is no particular limitation as long as it does not hinder the reaction and dissolves the starting materials to some extent. Ethers such as diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; or nitriles such as acetonitrile, Preferably ethers (especially tetrahydrofuran)
Or amides (particularly dimethylformamide). The reaction temperature varies depending on the raw material compounds, reagents, and the like.
(Preferably −10 ° C. to 100 ° C.), and in the reaction between the active ester compound and the alcohol, −20 ° C. to 1 ° C.
00 ° C. (preferably 0 ° C. to 50 ° C.). The time required for the reaction varies depending on the starting compound, the reagent and the reaction temperature, but is usually 30 minutes to 80 hours (preferably 1 hour to 48 hours) for both reactions. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method.
For example, after completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent has been distilled off, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extraction is performed. The obtained organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the desired compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The halogenating agent used in the reaction (f3) is not particularly limited as long as it is generally used in the art of organic synthetic chemistry. Examples thereof include oxalyl chloride, thionyl chloride, oxy It can be phosphorus chloride or phosphorus pentachloride, preferably thionyl chloride.

The solvent used in both reactions is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene. Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or diethyl ether, diisopropyl ether,
It can be an ether such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, preferably an ether (especially tetrahydrofuran). The reaction temperature varies depending on the starting compound, the reagent, and the like.
The temperature is from 0 ° C to 150 ° C (preferably from -10 ° C to 100 ° C), and from -20 ° C to 100 ° C (preferably from 0 ° C to 50 ° C) in the reaction between an acid halide and an alcohol. The time required for the reaction varies depending on the starting compound, the reagent and the reaction temperature, but is usually 30 minutes to 80 hours (preferably 1 hour to 48 hours) for both reactions. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent has been distilled off, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extraction is performed. The obtained organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the desired compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Reaction (g): The reaction for converting an alkoxycarbonyl group into a carbamoyl group in the reaction (g) is performed by a method well known in synthetic organic chemistry. For example, the reaction is performed by reacting ammonia gas or concentrated aqueous ammonia in an inert solvent.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol. Diamines such as N, N, N ', N'-tetramethylethylenediamine; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide or hexamethylphosphorous triamide; or dimethylsulfoxide Or sulfoxides such as sulfolane, preferably ethers or alcohols, more preferably ethers (especially Tiger is a hydro furan).

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -10 ° C to 100 ° C, preferably from 0 ° C to 50 ° C. The reaction time depends on the starting compound, reagent,
Although it varies depending on the reaction temperature, it is usually 10 minutes to 10 hours, preferably 30 minutes to 3 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent has been distilled off, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extraction is performed. After washing the organic layer
The target compound can be obtained by drying over anhydrous magnesium sulfate or the like and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Reaction (h): The reaction for converting a carboxy group to a carbamoyl group in the reaction (h) is performed by a method well known in synthetic organic chemistry. For example, it is carried out by condensing with ammonia in an inert solvent according to a conventional method in peptide synthesis, for example, an azide method, an active ester method, a mixed acid anhydride method or a condensation method (preferably a mixed acid anhydride method). . In the above method, the azide method is a method in which hydrazine and -10 to 100 ° C. The reaction is carried out by reacting an amino acid hydrazide obtained by reacting at a temperature of 0 ° C. (preferably 0 ° C. to 50 ° C.) with a nitrite compound to convert it to an azide compound, followed by treatment with ammonia. The nitrite compound used is, for example, an alkali metal nitrite such as sodium nitrite or an alkyl nitrite such as isoamyl nitrite. The reaction is suitably carried out in an inert solvent, the solvent used being amides such as, for example, formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide;
Sulfoxides such as dimethylsulfoxide or sulfolane; or pyrrolidones such as N-methylpyrrolidone, preferably amides (particularly dimethylformamide). The two steps of this reaction (azidation and reaction with ammonia) are usually performed in one reaction solution. The reaction temperature varies depending on the starting compounds, reagents, and the like, but the azidation step is usually -70 ° C to 50 ° C (preferably -50 ° C to 0 ° C), and the reaction with ammonia is -70 ° C to The temperature is 50 ° C (preferably -10 ° C to 10 ° C). The time required for the reaction varies depending on the starting compound, the reagent and the reaction temperature. Usually, the azidation step is 5 minutes to 3 hours (preferably 10 minutes to 1 hour), and the reaction with ammonia is 5 hours. To 7 days (preferably 10 hours to 5 days). After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent is distilled off, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound,
The extracted organic layer is washed with water, dried over anhydrous magnesium sulfate or the like, and the target compound is obtained by distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography. The active ester method is carried out by reacting with an active esterifying agent in an inert solvent to produce an active ester, and then reacting with ammonia in an inert solvent. The solvent used in both reactions does not inhibit the reaction,
There is no particular limitation as long as it dissolves the starting material to some extent. For example, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran,
Ethers such as dioxane, dimethoxyethane or diethylene glycol dimethyl ether; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; or nitriles such as acetonitrile, preferably ethers ( Especially tetrahydrofuran) or amides (especially dimethylformamide). The active esterifying agent used is, for example, an N-hydroxy compound such as N-hydroxysuccinimide, 1-hydroxybenzotriazole or N-hydroxy-5-norbornene-2,3-dicarboximide or dipyridyl disulfide. The active esterification reaction is suitably performed in the presence of a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or triphenylphosphine. The reaction temperature varies depending on the starting compounds, reagents, and the like, but is generally -70 ° C to 150 ° C (preferably -10 ° C) in the active esterification reaction.
To 100 ° C.), and -20 ° C. to 100 ° C. (preferably 0 ° C.) in the reaction of the active ester compound with ammonia.
To 50 ° C.). The time required for the reaction depends on the starting compound,
Although it varies depending on the reagent and the reaction temperature, both reactions are usually performed for 30 minutes to 80 hours (preferably 1 hour to 48 hours). After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent has been distilled off, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extraction is performed. The obtained organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the desired compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography. The mixed acid anhydride method is to react a mixed acid anhydride in an inert solvent in the presence of a base to produce a mixed acid anhydride, and then react the mixed acid anhydride with ammonia in an inert solvent. Done. The solvent used in the reaction for producing the mixed acid anhydride is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.For example, methylene chloride, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; or formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric acid It can be an amide such as a triamide, preferably an ether (particularly tetrahydrofuran).
Mixed acid anhydride agents include, for example, C ₁ -C ₄ alkyl halogenoformates such as ethyl chloroformate or isobutyl chloroformate, C ₁ -C ₅ alkanoyl halides such as pivaloyl chloride, or diethyl cyanophosphoric acid or diphenyl. be a C ₁ -C ₄ alkyl or di-C ₆ -C ₁₄ aryl cyanophosphate such as cyanophosphonate, preferably,
C ₁ -C ₄ alkyl halogenoformate (especially isobutyl chloroformate). The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; or triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino ) Pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nona-
5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.
4.0] Organic amines such as undec-7-ene (DBU), preferably organic amines (especially triethylamine). The reaction temperature in the reaction for producing the mixed acid anhydride varies depending on the starting compounds, reagents and the like, but is usually -50 ° C to 100 ° C (preferably -10 ° C to 50 ° C). The reaction time in the reaction for producing the mixed acid anhydride varies depending on the starting compounds, the reagents, and the reaction temperature, but is usually 5 minutes to 20 hours (preferably 10 minutes to 1 hour)
0 hours). The solvent used in the reaction between the mixed acid anhydride and ammonia is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether or amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, preferably ethers ( Especially tetrahydrofuran). The reaction temperature in the reaction between the mixed acid anhydride and ammonia varies depending on the starting compounds, reagents and the like, but is usually from -30 ° C to 100 ° C (preferably from 0 ° C to 8 ° C).
0 ° C). The reaction time in the reaction between the mixed acid anhydride and ammonia varies depending on the starting compounds, reagents and reaction temperature, but is usually from 5 minutes to 24 hours (preferably from 10 minutes to 5 hours). After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent has been distilled off, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extraction is performed. The obtained organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the desired compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography. The condensation method is carried out by directly reacting with ammonia in an inert solvent in the presence of a condensing agent. The condensing agent used is, for example, dicyclohexylcarbodiimide, carbonyldiimidazole or 1-methyl-2-
It can be chloro-pyridinium iodide-triethylamine, preferably dicyclohexylcarbodiimide. This reaction can be carried out under the same conditions as in the above-mentioned reaction for producing an active ester. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method.
For example, after completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent has been distilled off, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extraction is performed. The obtained organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the desired compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Reaction (i): The reaction for converting a carbamoyl group to a cyano group in the reaction (i) is performed by a method well known in synthetic organic chemistry. For example, the reaction is performed by reacting with a dehydrating agent in an inert solvent. The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; benzene, toluene or Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether Ethers such as methyl acetate or ethyl acetate; ketones such as acetone; formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide or hexame Amides such as triphosphorous triamide; or sulfoxides such as dimethyl sulfoxide or sulfolane, preferably ethers, amides or sulfoxides, more preferably amides (particularly dimethyl Formamide). The dehydrating agent used can be, for example, phosphorus oxychloride, trifluoroacetic anhydride, methanesulfonyl chloride, paratoluenesulfonyl chloride or phosphorus pentoxide, preferably phosphorus oxychloride. The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually -30.
C. to 100.degree. C., preferably 0.degree. C. to 50.degree. The reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually 5 minutes to 10 hours, preferably 10 minutes.
Minutes to 3 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the solvent is distilled off, water is poured into the reaction solution, a water-immiscible solvent (for example, benzene, ether, ethyl acetate, etc.) is added and extracted, the organic layer is washed with water, dried over anhydrous magnesium sulfate, etc. Is distilled off to obtain the desired compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Reaction (j): The reaction of converting the alkoxy group on the aromatic ring into a hydroxyl group in the reaction (j) is performed by a method well known in synthetic organic chemistry. For example, the reaction is performed by reacting with aluminum chloride in an inert solvent.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; or esters such as methyl acetate or ethyl acetate; Preferred are halogenated hydrocarbons (particularly methylene chloride).

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -10 ° C to 100 ° C, preferably from 10 ° C to 50 ° C. The reaction time varies depending on the starting compounds, reagents, reaction temperature and the like, but is usually 1 hour to 7 hours.
2 hours, preferably 2 hours to 30 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the solvent is distilled off, water is poured into the reaction solution, if necessary, neutralized, and a water-immiscible solvent (for example, benzene, ether, ethyl acetate, etc.) is added and extracted. After drying with magnesium or the like, the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Reaction (k): The reaction for acylating a hydroxyl group or an amino group in the reaction (k) is carried out by a method well known in organic synthetic chemistry. For example, in an inert solvent in the presence or absence (preferably in the presence) of a base, an acylating agent (preferably an alkanoyl halide, a mixed acid anhydride of formic acid and acetic acid, an alkanecarboxylic anhydride, an arylcarbonyl (Halide or arylcarboxylic anhydride). The alkanoyl halides used are, for example, those having 2 to 6 carbon atoms such as acetyl chloride, propionyl chloride, butyryl chloride, butyryl bromide, isobutyryl chloride, valeryl chloride, pivaloyl chloride or hexanoyl chloride. it is straight-chain or branched-chain alkanoyl halide, preferably a C ₂ -C ₄ alkanoyl chloride, more preferably acetyl chloride. The alkanecarboxylic anhydride used is, for example, a linear chain having 4 to 12 carbon atoms such as acetic anhydride, propionic anhydride, butanoic anhydride, valeric anhydride, pivalic anhydride, pentanoic anhydride or hexanoic anhydride. or branched alkanes carboxylic acid anhydride obtained, preferably a C ₄ -C ₈ alkanecarboxylic acid anhydride, more preferably acetic anhydride. The arylcarbonyl halide used is, for example, benzoyl chloride, benzoyl bromide, fluorobenzoyl chloride, chlorobenzoyl chloride, dichlorobenzoyl chloride, toluoyl chloride, anisoyl chloride, indenoyl chloride, indenoyl bromide, naphthoyl chloride, naphthoyl bromide, it is a C ₆ -C ₁₀ aryl carboxylic acid halide such as phenanthrylethynyl thread noil chloride or anthracenyl noil chloride, preferably benzoyl chloride. The arylcarboxylic anhydrides used are, for example, C, such as benzoic anhydride, fluorobenzoic anhydride, chlorobenzoic anhydride, methylbenzoic anhydride, methoxybenzoic anhydride, indenylcarboxylic anhydride or naphthylcarboxylic anhydride. ₆ -C ₁₀ aryl carboxylic acid anhydride and is obtained, preferably a benzoic anhydride. The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; or triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-
Dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8
Organic amines such as -diazabicyclo [5.4.0] undec-7-ene (DBU), preferably organic amines (especially triethylamine, diisopropylethylamine, pyridine or 4- (N, N-dimethyl). Amino) pyridine). The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene, toluene Or aromatic hydrocarbons such as xylene;
Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; acetone, methyl ethyl ketone Ketones; or amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, preferably ethers (particularly tetrahydrofuran).

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -50 ° C to 100 ° C (preferably 0 ° C
To 50 ° C.). The reaction time depends on the starting compound, reagent,
Although it varies depending on the reaction temperature, it is usually 5 minutes to 20 hours (preferably 10 minutes to 10 hours). After the reaction,
The target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent has been distilled off, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extraction is performed. The obtained organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the desired compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Reaction (l): The reaction for aralkylating a hydroxyl group or an amino group in the reaction (l) is carried out by a method well known in synthetic organic chemistry. For example, the reaction is carried out by reacting with an aralkyl halide in an inert solvent in the presence or absence (preferably in the presence) of a base. C ₆ -C ₄₈ aralkyl halide used is, for example, benzyl chloride, benzyl bromide, 4-chlorobenzyl chloride, 4-chlorobenzyl bromide, 4-bromobenzyl chloride, 4-bromobenzyl bromide,
2,4-difluorobenzyl chloride, 2,4-dichlorobenzyl chloride, 2,4-dichlorobenzyl bromide, 4-methoxybenzyl chloride, 4-methoxybenzyl bromide, trityl chloride, trityl bromide, dimethoxytrityl chloride or α-
C ₆ -C which may have 1 to 3 substituents which are the same or different and are selected from the group consisting of halogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy, such as naphthyldiphenylmethyl chloride. ₄₈ aralkyl halides, preferably halogen, C ₁ -C ₄ alkyl and C _1-
Benzyl chloride or benzyl bromide, which may have 1 to 3 substituents selected from the group consisting of C ₄ alkoxy, which are the same or different, more preferably benzyl chloride or benzyl bromide.

The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal hydrogen carbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; lithium hydride Alkali metal hydrides such as sodium hydroxide or potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine , Pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nona-5
-Ene (DBN), 1,4-diazabicyclo [2.2.
2] organic amines such as octane (DABCO) or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU); alkyllithiums such as methyllithium, ethyllithium or butyllithium; Can be lithium alkylamides such as lithium diisopropylamide or lithium dicyclohexylamide, preferably alkali metal carbonates, alkali metal hydrides or organic amines, more preferably alkali metal carbonates (Especially sodium carbonate or potassium carbonate) or alkali metal hydrides (especially sodium hydride).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone; or formamide, dimethylformamide;
It may be an amide such as dimethylacetamide or hexamethylphosphoric triamide, preferably an amide (especially dimethylformamide).

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -50 ° C to 100 ° C (preferably 0 ° C).
To 50 ° C.). The reaction time depends on the starting compound, reagent,
Although it varies depending on the reaction temperature, it is usually 5 minutes to 24 hours (preferably 10 minutes to 5 hours). After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent is distilled off, neutralized if necessary, and then mixed with a water-immiscible solvent (eg, benzene, ether,
The target compound is extracted by adding ethyl acetate and the like, and the extracted organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Reaction (m): The reaction for converting a nitro group into an amino group in the reaction (m) is performed by a method well known in organic synthetic chemistry. For example, the reaction is carried out by reacting with zinc in an inert solvent in the presence of acetic acid. The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; benzene, toluene Or an aromatic hydrocarbon such as xylene; a halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether Ethers such as methanol; alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol;
Diamines such as N, N, N ', N'-tetramethylethylenediamine; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide or hexamethylphosphorous triamide; such as dimethylsulfoxide or sulfolane Sulfoxides; or water or a mixed solvent of water and the above solvent, preferably water. The reaction temperature is the starting compound,
Depends on reagents, etc., usually -10 ° C to 100 ° C
And preferably from 0 ° C to 50 ° C. The reaction time varies depending on the starting compounds, reagents and reaction temperature.
It is from 0 minutes to 10 hours, preferably from 30 minutes to 3 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or water is poured into a residue obtained by distilling the solvent,
After neutralization, a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound,
The extracted organic layer is washed with water, dried over anhydrous magnesium sulfate or the like, and the target compound is obtained by distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

[0159] Reaction (n): reaction for removing the protective group of amino group is contained in at R ³ a and the like in the reaction (n), wherein the A
It is performed under the same conditions as in the three steps.

The compound having the general formula (II), which is a starting material compound of the present invention, is a known compound or can be produced according to a known method [for example, Chemical Abstract, Vol. 74, No. 1255
21 (1970) [ Chem. Abstr. , 74 , 125521 (197
0).], Sankyo Institute Annual Report, Vol. 22, pp. 215 (19
70), Agricultural and Biological Chemistry, 50, 1831 (1986)
Agric. Biol. Chem., EN , 50 , 1831 (1986).], Canadian Journal of Chemistry, Vol. 48,
1371 (1970) [ Can. J. Chem. , 48 , 1371 (19)
70).], JP-A-59-216881, and JP-B-43.
-14704 publication etc.]. Further, the compound having the general formula (IV) or the general formula (IVa) is a known compound or can be produced according to a known method. [For example, Synthesis, p. 366 (1990)
[ Synthesis , 366 (1990).], Journal of Medicinal Chemistry, 34, 1258 (199).
1 year) [ J. Med. Chem. , 34 , 1258 (1991)] etc.]. Compound (II), which is a starting material compound of the present invention, is a known compound or can be produced according to a known method. The compound can be separately produced by reacting the compound according to the method described below.

[0161]

Embedded image

[0162]

Embedded image

[0163]

Embedded image

In the above formula, R¹ , R^Two And Z are as described above.
Has the same meaning as^Two _aIs R^TwoSpecific substitutions in
Group (the substituent group is a halogen atom, C₁ -C₆ Alkyl
Group, halogen or C₁ -C₆ Substituted with alkoxy
C₁ -C₆ Alkyl group, C _Two -C₆ Alkenyl group, C
_Two -C₆ Alkynyl group, C_Three -C_TenCycloalkyl group,
C_Three -C_TenCycloalkenyl group, C_Two -C₆ Arcanoy
And C₁ -C₆ From an alkoxycarbonyl group
You. ) And R^Four Is C₁ -C₆ Shows an alkyl group.

The alkyl group for R ⁴ includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-pentyl, Methylbutyl group, neopentyl group, 1-ethylpropyl group, hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2 1 to 6 carbon atoms such as dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl it is a straight or branched chain alkyl group, preferably a C ₁ -C ₄ alkyl group, more preferably a methyl group or an ethyl group.

Method D is a method for producing compound (II) which is a starting material compound in method A or method B.

In the step D1, the compound having the general formula (VI) is reacted with an active esterifying agent in (a) an inert solvent in an inert solvent to produce an active ester. Or (b)
After reacting with a halogenating agent in an inert solvent and then reacting with compound (VII), or (c) reacting with compound (VII) in an inert solvent in the presence of an acid to obtain a compound represented by the general formula ( This is a step of producing a compound having VIII). The step D1 (a) and the step D1 (b) correspond to the reaction (f2) and the reaction (f) in the step C1, respectively.
This is performed under the same conditions as in 3).

The acid used in the step D1 (c) is
In general, there is no particular limitation so long as it is commonly used in the art of organic synthetic chemistry. Mineral acids; sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid; or fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid or maleic acid It can be a carboxylic acid such as an acid, preferably a mineral acid, especially sulfuric acid. The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; benzene, toluene Or aromatic hydrocarbons such as xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone; methanol, ethanol, propanol, isopropanol , Butanol or alcohol such as isobutanol or amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, preferably alcohols (particularly methanol or ethanol). The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually -5.
It is 0 ° C to 150 ° C (preferably 20 ° C to 100 ° C). The reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually 5 minutes to 24 hours (preferably 10 minutes to 5 hours). After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent is distilled off, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound,
The extracted organic layer is washed with water, dried over anhydrous magnesium sulfate or the like, and the target compound is obtained by distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

In the step D2, the compound (V) is dissolved in an inert solvent.
III) is reacted with a halogen molecule to obtain a compound of the general formula (IX)
This is a step of producing a compound having The halogen molecules used can be, for example, chlorine or bromine molecules,
Preferably it is a bromine molecule. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene, toluene Or aromatic hydrocarbons such as xylene;
Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; acetone, methyl ethyl ketone Ketones; alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol or amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, preferably halogenated. Hydrocarbons (especially chloroform or carbon tetrachloride). The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -50 ° C to 100 ° C (preferably 0 ° C
To 50 ° C.). The reaction time depends on the starting compound, reagent,
Although it varies depending on the reaction temperature, it is usually 5 minutes to 12 hours (preferably 10 minutes to 5 hours). After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent has been distilled off, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extraction is performed. The obtained organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the desired compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Step D3 is carried out in an inert solvent in the presence or absence (preferably in the presence of a base) of a compound (IX).
Is reacted with hydroxylamine or a mineral acid salt of hydroxylamine (preferably a salt of hydroxylamine) to produce a compound (II). Hydroxylamine mineral salts used are, for example, hydroxylamine hydrofluoride, hydroxylamine hydrochloride, hydroxylamine hydrobromide, hydroxylamine hydroiodide, hydroxylamine nitrate, hydroxylamine perchlorate, hydroxyl sulfate. It can be an amine or hydroxylamine phosphate, preferably hydroxylamine hydrochloride. Method E is a method for separately producing compound (II) which is a starting material compound in Method A or Method B. Eth
One step is a step of producing a compound having the general formula (XII) by reacting the compound (X) with a compound having the general formula (XI) in an inert solvent in the presence of a base. The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Or aromatic hydrocarbons such as xylene; methylene chloride;
Halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; or such as dimethyl sulfoxide or sulfolane Sulfoxides, preferably aromatic hydrocarbons, halogenated hydrocarbons or ethers, more preferably aromatic hydrocarbons (particularly benzene) or ethers (particularly tetrahydrofuran or dioxane) ).

The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate;
Alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; sodium hydroxide,
Alkali metal hydroxides such as potassium hydroxide or lithium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; sodium methyl mercaptan or sodium ethyl mercaptan Alkali metals such as mercaptans; triethylamine, tributylamine, diisopropylethylamine,
N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline,
N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8
Organic amines, such as diazabicyclo [5.4.0] undec-7-ene (DBU); alkyllithiums, such as methyllithium, ethyllithium or butyllithium; lithium, such as lithium diisopropylamide or lithium dicyclohexylamide It may be an alkylamide, preferably a lithium alkylamide (especially lithium diisopropylamide) or an organic amine (especially 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU)). . The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually from -100 ° C to 1 ° C.
It is 00 ° C, preferably -70 ° C to 50 ° C. The reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after distilling off the solvent, pouring water into the reaction solution, making the reaction solution weakly acidic,
A water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added and extracted, the organic layer is washed with water, dried over anhydrous magnesium sulfate, etc., and the solvent is distilled off to obtain the desired compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Step E2 is carried out in an inert solvent in the presence or absence (preferably in the presence of a base) of a compound (XI)
A step of reacting I) with hydroxylamine or a mineral salt of hydroxylamine (preferably a salt of hydroxyamine) to produce compound (II), which is carried out under the same conditions as in Step D3 .

[0173] Method F is, in the intermediates of Method E (XII), R ² is a halogen atom, C ₁ -C ₆ alkyl group, C ₁ substituted with halogen or C ₁ -C ₆ alkoxy
-C ₆ alkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆
Alkynyl group, C ₃ -C ₁₀ cycloalkyl group, C ₃ -
Compounds which are a C ₁₀ cycloalkenyl group, a C ₂ -C ₆ alkanoyl group or a C ₁ -C ₆ alkoxycarbonyl group (X
This is a method for separately producing IIa).

In the step F1, the compound having the general formula (XIII) is converted to a compound of the general formula (XIII) in an inert solvent in the presence of a base.
This is a step of producing compound (XIIa) by reacting with compound having (IV), and is carried out under the same conditions as in Step E1.

The isoxazole derivative (I) of the present invention
Since it has an excellent A-type monoamine oxidase inhibitory activity and low toxicity, it has depression, Parkinson's disease, Alzheimer-type dementia (such as cognitive impairment based on Alzheimer's disease) or cerebrovascular dementia (cognition based on cerebrovascular dementia). It is useful as a therapeutic or prophylactic (especially a therapeutic agent) for neurological diseases (particularly depression) such as disorders.

When the compound (I) of the present invention or a pharmacologically acceptable salt thereof is used as a therapeutic or prophylactic agent for the above-mentioned neurological diseases, the compound itself or an appropriate pharmacologically acceptable salt thereof may be used. It can be mixed with a form, diluent and the like, and administered orally with tablets, capsules, granules, powders or syrups or parenterally with injections or suppositories.

These preparations contain excipients (eg, lactose,
Sugar derivatives such as white sugar, glucose, mannitol, sorbitol; corn starch, potato starch,
α-starch, starch derivatives such as dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; organic excipients such as pullulan: and light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, and metasilicate aluminate Inorganic excipients such as silicate derivatives such as magnesium; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; sulfates such as calcium sulfate. ), Lubricants (eg, stearic acid metal salts such as stearic acid, calcium stearate, magnesium stearate; talc; colloidal silica; waxes such as veegum, gay wax; boric acid; adipic acid; Sodium sulfate; DL leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as anhydrous silicic acid and silicic acid hydrate; Derivatives can be mentioned.) Binders (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and the same compounds as the above-mentioned excipients), disintegrants (for example, , Low-substituted hydroxypropyl Cellulose derivatives such as loin, carboxymethylcellulose, carboxymethylcellulose calcium, and internally crosslinked sodium carboxymethylcellulose; and chemically modified starch celluloses such as carboxymethylstarch, sodium carboxymethylstarch, and crosslinked polyvinylpyrrolidone.) Stabilizers (paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal;
Dehydroacetic acid; and sorbic acid. ), Flavoring agents (for example, commonly used sweeteners, sour agents, flavors, etc.) and diluents can be used in a well-known method. The dosage varies depending on the condition, age, etc., but in the case of oral administration, the lower limit is 1 mg (preferably 10 mg) and the upper limit is 2000 mg (preferably 400 mg) per dose. 0.1 mg per dose (preferably 1 m
g), it is desirable to administer an upper limit of 500 mg (preferably 300 mg) to an adult 1 to 6 times a day according to symptoms. Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, Test Examples, and Formulation Examples, but the scope of the present invention is not limited thereto.

[0178]

EXAMPLES Example 1 3- (2-Aminoethoxy) -5-phenylisoxazole hydrochloride (Exemplary Compound No. 1) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-Phenylisoxazole Triphenylphosphine (0.87 g) was dissolved in tetrahydrofuran (10 ml), and diethyl azodicarboxylate (0.57 g) was added dropwise with stirring under ice-cooling.
Stirred for minutes. 3-Hydroxy-5-phenylisoxazole (0.48 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.48 g) were added, and the mixture was stirred under ice-cooling for 10 minutes and then at room temperature for 24 hours. Stirred. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 4/1), and crystallized from isopropyl ether to give the desired compound (0.6
(3 g, 69%) as colorless crystals. Melting point: 125-126 ° C; IR spectrum (KBr) ν _max cm ^-1 : 332
2,1721, 1710, 1619; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.56 (2H, q, J = 5.1H
z), 4.35 (2H, t, J = 5.1 Hz), 4.9
4 (1H, brs), 6.14 (1H, s), 7.43
−7.51 (3H, m), 7.71-7.74 (2H,
m).

(B) 3- (2-aminoethoxy) -5
-Phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.5
0 g) in 4N hydrochloric acid / 1,4-dioxane solution (4.0 g).
ml) and stirred at room temperature for 15 minutes. The precipitated crystals were collected by filtration and washed with ethyl acetate to give the target compound (0.39 g, 99%) as colorless crystals. Melting point: 215-218 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 313
2,2963,2810,2756,1620,159
7,1579; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.26 (2H, t, J = 5.1 Hz), 4.45 (2
H, t, J = 5.1 Hz), 6.85 (1H, s),
7.51-7.57 (3H, m), 7.84-7.87
(2H, m), 8.25 (3H, brs).

Example 2 3- (2-aminoethoxy) -4-chloro-5-phenylisoxazole hydrochloride (Exemplary Compound No .: 5) (a) 3- (2- (N-tert-butoxycarbonylamino) ) Ethoxy) -4-chloro-5-phenylisoxazole 4-chloro-3-hydroxy-5-phenylisoxazole (0.58 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.48 g) ) Was reacted in the same manner as in Example 1 (a),
The target compound (0.73 g, 72%) was obtained as colorless crystals. Melting point: 115-116 ° C; IR spectrum (KBr) ν _max cm ^-1 : 334
6,1720,1709,1616; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.61 (2H, q, J = 5.1H
z), 4.42 (2H, t, J = 5.1 Hz), 4.9
7 (1H, brs), 7.46-7.53 (3H,
m), 7.94-8.00 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Chloro-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-chloro-5-phenylisoxazole (0.54 g) was prepared in Example 1 (b). The target compound (0.41 g,
93%) as colorless crystals. Melting point: 204-207 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 297
1,905,2848,2775,1606,157
5,1534; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.31 (2H, t, J = 5.1 Hz), 4.56 (2
H, t, J = 5.1 Hz), 7.59-7.67 (3
H, m), 7.92-7.97 (2H, m), 8.27
(3H, brs). Example 3 3- (2-aminoethoxy) -5- (4-chlorophenyl) isoxazole hydrochloride (Exemplary Compound No .: 14
3) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl)
Isoxazole 5- (4-chlorophenyl) -3-hydroxyaminoisoxazole (0.58 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.48 g)
Was reacted in the same manner as in Example 1 (a) and post-treated to give the target compound (0.69 g, 68%) as colorless crystals. Melting point: 128-129 ° C; IR spectrum (KBr) ν _max cm ^-1 : 337
8,1683,1622; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.56 (2H, q, J = 5.1H
z), 4.35 (2H, t, J = 5.1 Hz), 4.9
3 (1H, brs), 6.14 (1H, s), 7.43
(2H, d, J = 8.7 Hz), 7.66 (2H, d,
J = 8.7 Hz).

(B) 3- (2-aminoethoxy) -5
-(4-Chlorophenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl) isoxazole (0.54 g) was reacted in the same manner as in Example 1 (b). And after-treatment, the target compound (0.43 g,
98%) as colorless crystals. Melting point: 218-223 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 313
5,2998,2809,1618,1603,159
4,1575,1567; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.26 (2H, t, J = 5.1 Hz), 4.45 (2
H, t, J = 5.1 Hz), 6.91 (1H, s),
7.63 (2H, d, J = 8.7 Hz), 7.89 (2
H, d, J = 8.7 Hz), 8.25 (3, brs).

Example 4 3- (2-aminoethoxy) -4-isopropyl-5
Phenylisoxazole hydrochloride (Exemplary compound number:
9) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isopropyl-5-phenylisoxazole 3-hydroxy-4-isopropyl-5-phenylisoxazole (0.50 g) ) And 2- (N-tert-butoxycarbonylamino) ethanol (0.40 g)
Was reacted in the same manner as in Example 1 (a) and subjected to post-treatment to obtain the target compound (0.60 g, 69%) as colorless crystals. Melting point: 98-99 ° C; IR spectrum (KBr) ν _max cm ^-1 : 338
6,1686,1642; NMR spectrum (CDCl ₃ ) δ ppm: 1.2
9 (6H, d, J = 6.8), 1.46 (9H, s),
3.06 (1H, q, J = 6.8), 3.60 (2H,
q, J = 5.1 Hz), 4.38 (2H, t, J = 5.
1Hz), 4.85 (1H, brs), 7.42-7.
50 (3H, m), 7.55-7.60 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Isopropyl-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isopropyl-5-phenylisoxazole (0.50 g) in Example 1 (b) The target compound (0.39
g, 95%) as colorless crystals. Melting point: 202-210 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 297
5,2939,1642,1599,1575; NMR Spectrum (DMSO-d ₆₎ δppm:
1.26 (6H, d, J = 6.8 Hz), 3.04 (1
H, q, J = 6.8 Hz), 3.28 (2H, t, J =
5.1 Hz), 4.46 (2H, t, J = 5.1H)
z), 7.50-7.64 (5H, m), 8.26 (3
H, brs).

Example 5 3- (2-aminoethoxy) -5- (2-thienyl) isoxazole hydrochloride (Exemplary Compound No .: 535) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy ) -5- (2-Thienyl) isoxazole 3-hydroxy-5- (2-thienyl) isoxazole (0.42 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.40 g) were prepared in Example 1.
The target compound (0.63 g, 82%) was obtained as colorless crystals by reacting in the same manner as in (a) and performing post-treatment. Melting point: 129-130 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 332
3,1708,1694,1618; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.56 (2H, q, J = 5.1H
z), 4.34 (2H, t, J = 5.1 Hz), 4.9
3 (1H, brs), 6.05 (1H, s), 7.11
(1H, dd, J = 5.1 Hz, J = 3.7 Hz),
7.43-7.48 (2H, m).

(B) 3- (2-aminoethoxy) -5
-(2-Thienyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-thienyl) isoxazole (0.05 g) was reacted in the same manner as in Example 1 (b). Then, by post-treatment, the target compound (0.37 g, 95
%) As colorless crystals. Melting point: 278-283 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 310
8, 3086, 2993, 2978, 2913, 161
3,1596; NMR Spectrum (DMSO-d ₆₎ δppm:
3.25 (2H, t, J = 5.1 Hz), 4.44 (2
H, t, J = 5.1 Hz), 6.69 (1H, s),
7.25 (1H, dd, J = 5.5 Hz, J = 3.7H
z), 7.71 (1H, d, J = 3.7 Hz), 7.8
4 (1H, d, J = 5.5 Hz), 8.25 (3H, b
rs).

Example 6 3- (2-aminoethoxy) -4-chloro-5- (2-
Thienyl) isoxazole hydrochloride (Exemplary compound number: 539) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-thienyl) isoxazole 4-chloro-3-hydroxy-5 (2-thienyl) isoxazole (0.50 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.40 g)
Was reacted in the same manner as in Example 1 (a) and subjected to post-treatment to give the target compound (0.57 g, 66%) as colorless crystals. Melting point: 94-95 ° C; IR spectrum (KBr) ν _max cm ^-1 : 334
2,1718,1708,1622; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.60 (2H, q, J = 5.1H
z), 4.40 (2 h, t, J = 5.1 Hz), 4.9
6 (1H, brs), 7.19 (1H, dd, J = 5.
2 Hz, J = 3.6 Hz), 7.56 (1H, d, J =
5.2 Hz), 7.74 (1 H, d, 3.6 Hz).

(B) 3- (2-aminoethoxy) -4
Example of -chloro-5- (2-thienyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-chloro-5- (2-thienyl) isoxazole (0.40 g) The reaction and post-treatment were carried out in the same manner as in 1 (b) to give the desired compound (0.3
1 g, 95%) as colorless crystals. Melting point: 278-283 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 310
9,2960,2897,1626,1596,157
9; NMR spectrum (DMSO = d ₆ ) δ ppm:
3.30 (2H, t, J = 5.1 Hz), 4.54 (2
H, t, J = 5.1 Hz), 7.34 (1H, dd, J)
= 5.1 Hz, J = 3.6 Hz), 7.83 (1H,
d, J = 3.6 Hz), 8.01 (1H, d, J = 5.
1 Hz), 8.26 (3H, brs).

Example 7 3- (2-Aminoethoxy) -5- (3-pyridyl) isoxazole hydrochloride (Exemplary Compound No .: 1056) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy ) -5- (3-Pyridyl) isoxazole 3-hydroxy-5- (3-pyridyl) isoxazole (0.41 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.40 g) were prepared in Example 1.
The target compound (0.50 g, 65%) was obtained as colorless crystals by carrying out the same reaction as in (a) and post-treatment. Melting point: 97-98 ° C; IR spectrum (KBr) ν _max cm ^-1 : 324
9,3145,1712,1626; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.57 (2H, q, J = 5.1H
z), 4.37 (2H, t, J = 5.1 Hz), 4.9
4 (1H, brs), 6.25 (1H, s), 7.42
(1H, dd, J = 8.0 Hz, J = 4.9 Hz),
8.04 (1H, d, J = 8.0 Hz), 8.64 (1
H, d, J = 4.9 Hz), 8.97 (1H, s).

(B) 3- (2-aminoethoxy) -5
-(3-Pyridyl) isoxazole dihydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (3-pyridyl) isoxazole (0.48 g) was prepared in the same manner as in Example 1 (b). The target compound (0.41 g, 92
%) As colorless crystals. Melting point: 222-227 ° C; IR spectrum (KBr) ν _max cm ^-1 : 309
6,3068,3043,2967,2886,281
3,1641, 1597, 1539; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.26 (2H, q, J = 5.1 Hz), 4.48 (2
H, t, J = 5.1 Hz), 7.11 (1H, s),
7.77 (1H, dd, J = 8.0 Hz, J = 5.1H
z), 8.38 (3H, brs), 8.46 (1H,
d, J = 8.0 Hz), 8.79 (1H, d, J = 5.
1Hz), 9.21 (1H, s).

Example 8 3- (2-aminoethoxy) -4-chloro-5- (3-
Pyridyl) isoxazole hydrochloride (Exemplary Compound No .: 1061) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (3-pyridyl) isoxazole 4-chloro-3-hydroxy-5- (3-pyridyl) isoxazole (0.49 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.40 g)
Was reacted in the same manner as in Example 1 (a) and subjected to post-treatment to obtain the target compound (0.54 g, 63%) as colorless crystals. Melting point: 76-77 ° C; IR spectrum (KBr) ν _max cm ^-1 : 335
3,3248,1754,1721,1709,161
6; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
7 (9H, s), 3.62 (2H, q, J = 5.1H
z), 4.43 (2H, t, J = 5.1 Hz), 4.9
7 (1H, brs), 7.45 (1H, dd, J = 8.
0 Hz, J = 5.1 Hz), 8.24 (1H, ddd,
J = 8.0 Hz, J = 2.0 Hz, J = 1.5 Hz),
8.72 (1H, dd, J = 5.1 Hz, J = 1.5H
z), 9.24 (1H, d, J = 2.0 Hz).

(B) 3- (2-aminoethoxy) -4
Implement -chloro-5- (3-pyridyl) isoxazole dihydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-chloro-5- (3-pyridyl) isoxazole (0.40 g) The target compound (0.3) was reacted in the same manner as in Example 1 (b) and post-treated.
(5 g, 96%) as colorless crystals. Melting point: 205-210 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 310
3,3053,2937,2899,2875,282
3,2800,1634,1607,1590,154
1; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.31 (2H, q, J = 5.1 Hz), 4.59 (2
H, t, J = 5.1 Hz), 7.74 (1H, dd, J)
= 8.0 Hz, J = 5.1 Hz), 8.40 (1H, d
dd, J = 8.0 Hz, J = 2.0 Hz, J = 1.5 H
z), 8.40 (3H, brs), 8.82 (1H, d
d, J = 5.1 Hz, J = 1.5 Hz), 9.15 (1
H, d, J = 2.0 Hz).

Example 9 3- (2-Aminoethoxy) -5- (2-methoxyphenyl) isoxazole hydrochloride (Exemplary Compound No .: 35
7) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-methoxyphenyl) isoxazole Triphenylphosphine (0.45 g) is dissolved in tetrahydrofuran (5 ml), and ice-cooled. Under stirring, diethyl azodicarboxylate (0.27 ml) was added dropwise, and
After stirring for 0 minutes, 2- (N-tert-butoxycarbonylamino) ethanol (0.20 g) and 3-hydroxy-5- (2-methoxyphenyl) isoxazole (0.22 g) were added, and the mixture was added under ice cooling. After stirring for minutes, the mixture was stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4/1) to give the target compound (0.33 g, 86%) as colorless. As a solid. Melting point: 131-133 ° C; IR spectrum (KBr) ν _max cm ^-1 : 330
9, 1712, 1620; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.57 (2H, q, J = 5.2H
z), 3.95 (3H, s), 4.36 (2H, t, J
= 5.2 Hz), 4.96 (1H, brs), 6.43
(1H, s), 7.00 (1H, d, J = 7.8H
z), 7.06 (1H, t, J = 7.8 Hz), 7.4
1 (1H, ddd, J = 7.8 Hz, J = 7.8 Hz,
J = 1.7 Hz), 7.91 (1H, dd, J = 7.8)
Hz, J = 1.7 Hz).

(B) 3- (2-aminoethoxy) -5
-(2-Methoxyphenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-methoxyphenyl) isoxazole (0.31 g) was added to 4N hydrochloric acid / 1,4 -Dissolved in a dioxane solution (2.3 ml) and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized using a mixed solvent of ethanol and isopropanol to give the desired compound (0.21 g, 84%).
Was obtained as colorless crystals. Melting point: 160-162 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 300
0,2959,2837,1621,1614; NMR spectrum (DMSO-d ₆ ) δppm:
3.25 (2H, t, J = 5.1 Hz), 3.94 (3
H, s), 4.45 (2H, t, J = 5.1 Hz),
6.56 (1H, s), 7.11 (1H, t, J = 7.
8Hz), 7.23 (1H, d, J = 7.8Hz),
7.52 (1H, ddd, J = 7.8 Hz, J = 7.8
Hz, J = 1.7 Hz), 7.81 (1H, dd, J =
7.8 Hz, J = 1.7 Hz), 8.25 (3 H, br
s).

Example 10 3- (2-aminoethoxy) -5- (3-methoxyphenyl) isoxazole hydrochloride (Exemplary Compound No .: 36
3) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (3-methoxyphenyl) isoxazole 3-hydroxy-5- (3-methoxyphenyl) isoxazole (0.22 g) 2- (N-tert-butoxycarbonylamino) ethanol (0.20 g)
The target compound (0.31 g, 82%) was obtained as a colorless powder by reacting in the same manner as in Example 9 (a) and performing post-treatment. Melting point: 89-90 ° C; IR spectrum (KBr) ν _max cm ^-1 : 331
2,1710; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.56 (2H, q, J = 5.2H
z), 3.86 (3H, s), 4.35 (2H, t, J
= 5.2 Hz), 4.93 (1H, brs), 6.13
(1H, s), 6.96-7.00 (1H, m), 7.
26-7.42 (3H, m).

(B) 3- (2-aminoethoxy) -5
-(3-Methoxyphenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (3-methoxyphenyl) isoxazole (0.29 g) was the same as in Example 9 (b). And recrystallized using a mixed solvent of ethanol and isopropanol to obtain the desired compound (0.19
g, 83%) as colorless crystals. Melting point: 180-182 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 299
5,2976,2914,1591; NMR Spectrum (DMSO-d ₆₎ δppm:
3.26 (2H, t, J = 5.1 Hz), 3.84 (3
H, s), 4.45 (2H, t, J = 5.1 Hz),
6.88 (1H, s), 7.09-7.11 (1H,
m), 7.38-7.48 (3H, m), 8.28 (3
H, brs).

Example 11 3- (2-Aminoethoxy) -5- (4-methoxyphenyl) isoxazole hydrochloride (Exemplary Compound No .: 35
0) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-methoxyphenyl) isoxazole 3-hydroxy-5- (4-methoxyphenyl) isoxazole (0.22 g) 2- (N-tert-butoxycarbonylamino) ethanol (0.20 g)
The reaction and post-treatment were carried out in the same manner as in Example 9 (a) to give the desired compound (0.32 g, 84%) as a colorless powder. Melting point: 117-118 ° C; IR spectrum (KBr) ν _max cm ^-1 : 334
4,1719,1623; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.56 (2H, q, J = 5.2H
z), 3.86 (3H, s), 4.34 (2H, t, J
= 5.2 Hz), 4.95 (1H, brs), 6.02
(1H, s), 6.96 (2H, d, J = 8.9H)
z), 7.66 (2H, d, J = 8.9 Hz).

(B) 3- (2-aminoethoxy) -5
-(4-Methoxyphenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-methoxyphenyl) isoxazole (0.30 g) as in Example 9 (b) And recrystallized using a mixed solvent of ethanol and isopropanol to give the target compound (0.17
g, 71%) as colorless crystals. Melting point: 190-193 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 299
0, 2969, 2950, 2900, 1617; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.25 (2H, t, J = 5.1 Hz), 3.83 (3
H, s), 4.43 (2H, t, J = 5.1 Hz),
6.69 (1H, s), 7.09 (2H, d, J = 8.
9 Hz), 7.79 (2H, d, J = 8.9 Hz),
8.25 (3H, brs).

Example 12 3- (2-Aminoethoxy) -5- (2-chlorophenyl) isoxazole hydrochloride (Exemplary Compound No .: 11
1) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-chlorophenyl)
Isoxazole 5- (2-chlorophenyl) -3-hydroxy-isoxazole (0.23 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.20 g) were reacted in the same manner as in Example 9 (a), Post-treatment provided the target compound (0.35 g, 88%) as a colorless powder. Melting point: 125-127 ° C; IR spectrum (KBr) ν _max cm ^-1 : 333
3,1710,1697,1618; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.57 (2H, q, J = 5.2H
z), 4.37 (2H, t, J = 5.2 Hz), 4.9
6 (1H, brs), 6.59 (1H, s), 7.33
-7.43 (2H, m), 7.46-7.54 (1H,
m), 7.87-7.94 (1H, m). (B) 3- (2-Aminoethoxy) -5- (2-chlorophenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-chlorophenyl) isoxazole (0. 33g) was reacted in the same manner as in Example 9 (b), and recrystallized from isopropanol to obtain the desired compound (0.20 g, 74%) as colorless crystals. Melting point: 141-144 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 300
3,2965,1610; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.278 (2H, t, J = 5.1 Hz), 4.48
(2H, t, J = 5.1 Hz), 6.80 (1H,
s), 7.52-7.60 (2H, m), 7.68 (1
H, dd, J = 7.5 Hz, J = 1.9 Hz), 7.8
7 (1H, dd, J = 7.5 Hz, J = 1.9 Hz),
8.27 (3H, brs).

Example 13 3- (2-Aminoethoxy) -5- (3-chlorophenyl) isoxazole hydrochloride (Exemplary Compound No .: 12
5) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (3-chlorophenyl)
Isoxazole 5- (3-chlorophenyl) -3-hydroxy-isoxazole (0.23 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.20 g) were reacted in the same manner as in Example 9 (a). Post-treatment provided the target compound (0.34 g, 85%) as a colorless powder. Melting point: 117-119 ° C; IR spectrum (KBr) ν _max cm ^-1 : 338
5,1685; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.57 (2H, q, J = 5.2H
z), 4.36 (2H, t, J = 5.2 Hz), 4.9
3 (1H, brs), 6.16 (1H, s), 7.36
−7.44 (2H, m), 7.57-7.67 (1H,
m), 7.70 (1H, s).

(B) 3- (2-aminoethoxy) -5
-(3-chlorophenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (3-chlorophenyl) isoxazole (0.33 g) was reacted in the same manner as in Example 9 (b). After recrystallization from a mixed solvent of ethanol and isopropanol, the target compound (0.2
1 g, 78%) as colorless crystals. Melting point: 204-208 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 299
6,2980,2920,1619; NMR Spectrum (DMSO-d ₆₎ δppm:
3.26 (2H, t, J = 5.1 Hz), 4.45 (2
H, t, J = 5.1 Hz), 6.98 (1H, s),
7.56-7.63 (2H, m), 7.80-7.84
(1H, m), 7.96 (1H, s), 8.22 (3
H, brs).

Example 14 3- (2-Aminoethoxy) -4-methyl-5-phenylisoxazole hydrochloride (Exemplary Compound No. 6) (a) 3- (2- (N-tert-butoxycarbonylamino) ) Ethoxy) -4-methyl-5-phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.3
0 g) was dissolved in tetrahydrofuran (10 ml),
N-butyllithium / n- at -70 ° C under nitrogen atmosphere
Hexane solution (1.56 M, 1.4 ml) was added dropwise and 10
Stirred for minutes. Then, methyl iodide (0.09 ml) was added dropwise, and the mixture was stirred for 10 minutes. After the temperature was raised to 0 ° C., the reaction solution was poured into ice water, and the pH of the solution was adjusted to 6 using an aqueous solution of monopotassium phosphate. Thereafter, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4/1) to give the desired compound (0.29 g, 94%) as a colorless powder. Melting point: 118-120 ° C; IR spectrum (KBr) ν _max cm ^-1 : 333
4,2974,1719,1708; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 2.12 (3H, s), 3.59 (2
H, q, J = 5.1 Hz), 4.38 (2H, t, J =
5.1Hz), 4.94 (1H, brs), 7.40-
7.53 (3H, m), 7.69 (2H, d, J = 7.
9 Hz).

(B) 3- (2-aminoethoxy) -4
-Methyl-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-methyl-5-phenylisoxazole (0.29 g) was prepared in Example 9 (b). And then recrystallized using a mixed solvent of methanol and ethanol to give the target compound (0.18 g, 7
8%) as colorless crystals. Melting point: 245-250 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 300
3,2892,1516; NMR spectrum (DMSO-d ₆ ) δ ppm:
2.13 (3H, s), 3.28 (2H, t, J = 5.
1 Hz), 4.46 (2H, t, J = 5.1 Hz),
7.50-7.59 (3H, m), 7.73 (2H,
d, J = 7.2 Hz), 8.21 (3H, brs).

Example 15 3- (2-Aminoethoxy) -4-ethyl-5-phenylisoxazole hydrochloride (Exemplary Compound No. 7) (a) 3- (2- (N-tert-butoxycarbonylamino) ) Ethoxy) -4-ethyl-5-phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.3
g) and ethyl iodide (0.12 ml) in Example 14
The target compound (0.24 g, 73%) was obtained as a colorless oil by reacting in the same manner as in (a) and performing post-treatment. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 34
60, 2980, 1713; NMR spectrum (CDCl ₃ ) δ ppm: 1.2
1 (3H, t, J = 7.5 Hz), 1.46 (9H,
s), 2.56 (2H, q, J = 7.5 Hz), 3.5
9 (2H, q, J = 5.2 Hz), 4.38 (2H,
t, J = 5.2 Hz), 4.90 (1H, brs),
7.37-7.51 (3H, m), 7.64-7.68
(2H, m).

(B) 3- (2-aminoethoxy) -4
-Ethyl-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-ethyl-5-phenylisoxazole (0.21 g) was prepared in Example 9 (b). The target compound (0.12 g,
71%) as colorless crystals. Melting point: 210-215 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 296
8,2886,1518; NMR spectrum (DMSO-d ₆ ) δ ppm:
1.15 (3H, t, J = 7.5 Hz), 2.58 (2
H, q, J = 7.5 Hz), 3.29 (2H, t, J =
5.1 Hz), 4.46 (2H, t, J = 5.1H)
z), 7.51-7.59 (3H, m), 7.67-
7.70 (2H, m), 8.25 (3H, brs).

Example 16 3- (2-Aminoethoxy) -5-phenyl-4-propylisoxazole hydrochloride (Exemplary Compound No. 8) (a) 3- (2- (N-tert-butoxycarbonylamino) ) Ethoxy) -5-phenyl-4-propylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.3
g) and propyl iodide (0.29 ml) in Example 14
The target compound (0.22 g, 65%) was obtained as a colorless oil by reacting in the same manner as in (a) and performing post-treatment. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 34
60, 2966, 1713; NMR spectrum (CDCl ₃ ) δ ppm: 0.9
7 (3H, t, J = 7.4 Hz), 1.46 (9H,
s), 1.56-1.69 (2H, m), 2.51 (2
H, t, J = 7.6 Hz), 3.58 (2H, q, J =
5.2 Hz), 4.37 (2H, t, J = 5.2H)
z), 4.90 (1H, brs), 7.43-7.53
(3H, m), 7.65-7.68 (2H, m).

(B) 3- (2-aminoethoxy) -5
-Phenyl-4-propylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenyl-4-propylisoxazole (0.18 g) was prepared in Example 9 (b). The target compound (0.10 g,
71%) as colorless crystals. Melting point: 119-121 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 296
0, 2933, 2872, 1518; NMR spectrum (DMSO-d ₆ ) δ ppm:
0.91 (3H, t, J = 7.3 Hz), 1.51-
1.61 (2H, m), 2.54 (2H, t, J = 7.
7 Hz), 3.28 (2H, t, J = 5.1 Hz),
4.45 (2H, t, J = 5.1 Hz), 7.50-
7.59 (3H, m), 7.68-7.70 (2H,
m), 8.20 (3H, brs).

Example 17 3- (2-Aminoethoxy) -4-butyl-5-phenylisoxazole hydrochloride (Exemplary Compound No. 10) (a) 3- (2- (N-tert-butoxycarbonylamino) ) Ethoxy) -4-butyl-5-phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.3
g) and butyl iodide (0.17 ml)
The target compound (0.23 g, 66%) was obtained as a colorless oily substance by reacting and post-treating in the same manner as in (a). IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 34
60,2962,1713; NMR spectrum (CDCl ₃ ) δ ppm: 0.9
3 (3H, t, J = 7.3 Hz), 1.31-1.63
(4H, m), 1.46 (9H, s), 2.53 (2
H, t, J = 7.6 Hz), 3.58 (2H, q, J =
5.3Hz), 4.38 (2H, t, J = 5.3H)
z), 4.90 (1H, brs), 7.42-7.51
(3H, m), 7.65-7.68 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Butyl-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-butyl-5-phenylisoxazole (0.20 g) was prepared in Example 9 (b). The target compound (0.12 g,
75%) as colorless crystals. Melting point: 104-106 ° C; IR spectrum (KBr) ν _max cm ^-1 : 300
6,2963,2951,2931,869,151
6; NMR spectrum (DMSO-d ₆ ) δ ppm:
0.87 (3H, t, J = 7.3 Hz), 1.27 −
1.37 (2H, m), 1.47-1.55 (2H,
m), 2.57 (2H, t, J = 7.7 Hz), 3.2
8 (2H, t, J = 5.1 Hz), 4.46 (2H,
t, J = 5.1 Hz), 7.51-7.59 (3H,
m), 7.68-7.70 (2H, m), 8.23 (3
H, brs).

Example 18 3- (2-Aminoethoxy) -4-hexyl-5-phenylisoxazole hydrochloride (Exemplary Compound No .: 138
8) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-hexyl-5-phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5 -Phenylisoxazole (0.4
g) and hexyl iodide (0.23 ml)
The target compound (0.31 g, 61%) was obtained as a colorless powder by performing the same reaction as in (a) and performing post-treatment. IR spectrum (KBr) ν _max cm ^-1 : 338
7,2936,1715; NMR spectrum (CDCl ₃ ) δ ppm: 0.8
8 (3H, t, J = 6.6 Hz), 1.23-1.42
(6H, m), 1.46 (9H, s), 1.53-1.
70 (2H, m), 2.52 (2H, t, J = 7.7H
z), 3.58 (2H, q, J = 5.1 Hz), 4.3
7 (2H, t, J = 5.1 Hz), 4.90 (1H, b
rs), 7.40-7.51 (3H, m), 7.65-
7.68 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Hexyl-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-hexyl-5-phenylisoxazole (0.2 g) was prepared in Example 9 (b). The target compound (0.13 g,
81%) as colorless crystals. Melting point: 99-101 ° C; IR spectrum (KBr) ν _max cm ^-1 : 295
4,2930,1515; NMR spectrum (DMSO-d ₆ ) δ ppm:
0.83 (3H, t, J = 6.9 Hz), 1.18-
1.32 (6H, m), 1.48-1.55 (2H,
m), 2.56 (2H, t, J = 7.7 Hz), 3.2
8 (2H, t, J = 5.1 Hz), 4.45 (2H,
t, J = 5.1 Hz), 7.50-7.59 (3H,
m), 7.67-7.69 (2H, m), 8.16 (3
H, brs).

Example 19 3- (2-Aminoethoxy) -4-carboxy-5-phenylisoxazole hydrochloride (Exemplary Compound No .: 14
08) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carboxy-5-phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5 -Phenylisoxazole (2.0
0 g) in tetrahydrofuran (20 ml),
Butyl lithium (1.56
M hexane solution, 9.3 ml) was added dropwise and stirred for 10 minutes. Next, after bubbling carbon dioxide gas for 10 minutes, the temperature was raised to 0 ° C. The reaction solution was poured into ice water, the pH of the solution was adjusted to 6 using an aqueous solution of monopotassium phosphate, extracted with ethyl acetate, and the organic layer was washed with a saturated saline solution and then dried over anhydrous magnesium sulfate. Let dry. After filtration,
The solvent was distilled off under reduced pressure, and the obtained residue was washed with ether to obtain the target compound (2.18 g, 95%) as a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 298
2,1706; NMR Spectrum (DMSO-d ₆₎ δppm:
1.38 (9H, s), 3.38 (2H, q, J = 5.
7 Hz), 4.29 (2H, t, J = 5.7 Hz),
7.01 (1H, brs), 7.51-7.62 (3
H, m), 7.84-7.91 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Carboxy-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carboxy-5-phenylisoxazole (0.12 g) in Example 9 (b) The target compound (0.06
g, 60%) as colorless crystals. Melting point: 180-183 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 314
9, 2873, 2820, 1755, 1709; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.30 (2H, t, J = 5.3 Hz), 4.54 (2
H, t, J = 5.3 Hz), 7.54-7.65 (3
H, m), 7.85-7.87 (2H, m), 8.22
(3H, brs). Example 20 3- (2-aminoethoxy) -4-carbamoyl-5
Phenylisoxazole hydrochloride (Exemplary compound number:
1414) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carbamoyl-5-phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4 -Carboxy-5-phenylisoxazole (0.6 g) in tetrahydrofuran (6 ml)
And carbonyldiimidazole (0.31 g) was added under ice-cooling and stirring, followed by stirring at room temperature for 30 minutes.
Aqueous ammonia (1 ml) was added dropwise to the reaction solution,
Stirred for hours. The reaction solution was poured into ice water, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain the target compound (0.60 g, quantitative) as a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 343
9,3371,3149,1694,1680; NMR Spectrum (DMSO-d ₆₎ δppm:
1.39 (9H, s), 3.39 (2H, q, J = 5.
0 Hz), 4.30 (2H, t, J = 5.0 Hz),
7.38 (1H, brs), 7.51-7.57 (3
H, m), 7.71 (1H, brs), 7.91-7.
94 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Carbamoyl-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carbamoyl-5-phenylisoxazole (0.22 g) was prepared in Example 9 (b). The target compound (0.13
g, 72%) as colorless crystals. Melting point: 225-230 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 340
7, 3213, 2963, 2878, 1662; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.32 (2H, t, J = 4.9 Hz), 4.54 (2
H, t, J = 4.9 Hz), 7.52-7.60 (4
H, m), 7.77 (1H, brs), 7.92-7.
94 (2H, m), 8.29 (3H, brs).

Example 21 3- (2-Aminoethoxy) -4-cyano-5-phenylisoxazole hydrochloride (Exemplary Compound No .: 140
6) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-cyano-5-phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4 Carbamoyl-5-phenylisoxazole (0.38 g) was added to dimethylformamide (4
ml), phosphorus oxychloride (0.11 ml) was added dropwise at 5 ° C. under a nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into ice water and extracted with ethyl acetate,
The organic layer was washed with a saturated saline solution and dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/1) to give the desired compound (0.28 g, 7
8%) as a colorless solid. IR spectrum (KBr) ν _max cm ^-1 : 338
4,2237,1690,1680; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
7 (9H, s), 3.61 (2H, q, J = 5.2H
z), 4.43 (2H, t, J = 5.2 Hz), 4.9
7 (1H, brs), 7.52-7.64 (3H,
m), 8.01-8.05 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Cyano-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-cyano-5-phenylisoxazole (0.25 g) was prepared in Example 9 (b). The target compound (0.13 g,
(65%) as colorless crystals. Melting point: 200-205 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 296
7,2236,1611; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.32 (2H, t, J = 5.1 Hz), 4.60 (2
H, t, J = 5.1 Hz), 7.68-7.76 (3
H, m), 7.98-8.01 (2H, m), 8.29
(3H, brs). Example 22 3- (2-aminoethoxy) -4-methoxycarbonyl-5-phenylisoxazole hydrochloride (Exemplary Compound No .: 1412) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy ) -4-Methoxycarbonyl-5
-Phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carboxy-5-phenylisoxazole (0.2 g) in a mixed solution of methanol and benzene (1: 5, 10 ml) ) And trimethylsilyldiazomethane (0.6 ml, 2.0 M hexane solution) was added dropwise under ice-cooling, followed by stirring at room temperature for 30 minutes. The reaction solution was poured into ice water, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/1) to give the desired compound (0.17 g, 81%). %) As a colorless solid. IR spectrum (KBr) ν _max cm ^-1 : 335
5,1725,1691; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.62 (2H, q, J = 5.1H
z), 3.85 (3H, s), 4.43 (3H, t, J
= 5.1 Hz), 5.03 (1H, brs), 7.46.
−7.54 (3H, m), 7.87-7.91 (2H,
m).

(B) 3- (2-aminoethoxy) -4
-Methoxycarbonyl-5-phenylisoxazole
Hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-methoxycarbonyl-5-phenylisoxazole (0.16 g) was reacted as in Example 9 (b) and worked up. As a result, the target compound (0.08 g, 62%) was obtained as colorless crystals. Melting point: 195-198 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 314
8, 2870, 2848, 2821, 1708; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.30 (2H, t, J = 5.2 Hz), 3.77 (3
H, s), 4.54 (2H, t, J = 5.2 Hz),
7.56-7.66 (3H, m), 7.85-7.87
(2H, m), 8.24 (3H, brs).

Example 23 3- (2-Aminoethoxy) -4-methylaminocarbonyl-5-phenylisoxazole hydrochloride (Exemplary Compound No. 1416) (a) 3- (2- (N-tert-butoxy) Carbonylamino) ethoxy) -4-methylaminocarbonyl-5-phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carboxy-5-phenylisoxazole (0.2 g) And methylamine (30% methanol solution, 0.12 ml) were reacted in the same manner as in Example 20 (a), and post-treated to give the target compound (0.18 ml).
g, 87%) as a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 340
5,3369,1677; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
5 (9H, s), 2.97 (3H, d, J = 5.0H
z), 3.64 (2H, q, J = 5.1 Hz), 4.4
4 (2H, t, J = 5.1 Hz), 4.90 (1H, b
rs), 7.30 (1H, brs), 7.46-7.5.
0 (3H, m), 8.05-8.09 (2H, m).

(B) 3- (2-aminoethoxy) -4
Example of -methylaminocarbonyl-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-methylaminocarbonyl-5-phenylisoxazole (0.17 g) 14
The target compound (0.08 g, 57%) was obtained as colorless crystals by carrying out the same reaction as in (a) and post-treatment. Melting point: 223-226 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 310
2,2935,2879,1646; NMR spectrum (DMSO-d ₆ ) δ ppm:
2.78 (3H, d, J = 4.4 Hz), 3.32 (2
H, t, J = 4.8 Hz), 4.53 (2H, t, J =
4.8 Hz), 7.51-7.60 (3H, m), 7.
89-7.92 (2H, m), 8.18 (1H, d, J
= 4.4 Hz), 8.31 (3H, brs).

Example 24 3- (2-Aminoethoxy) -5- (4-chlorophenyl) -4-methylisoxazole hydrochloride (Exemplary Compound No .: 148) (a) 3- (2- (N-tercia) Libutoxycarbonylamino) ethoxy) -5- (4-chlorophenyl)
-4-Methylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl) isoxazole (0.25 g) and methyl iodide (0.06 ml)
Was reacted in the same manner as in Example 14 (a) and worked up to give the target compound (0.23 g, 89%) as a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 334
4,2980,1682; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 2.10 (3H, s), 3.58 (2
H, q, J = 5.2 Hz), 4.37 (2H, t, J =
5.2Hz), 4.90 (1H, brs), 7.45
(2H, d, J = 8.6 Hz), 7.63 (2H, d,
J = 8.6 Hz).

(B) 3- (2-aminoethoxy) -5
-(4-Chlorophenyl) -4-methylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl) -4-methylisoxazole (0.22 g ) Was reacted in the same manner as in Example 9 (b) and worked up to give the target compound (0.09 g, 50%) as colorless crystals. Melting point: 248-253 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 302
0,2991,884,1513; NMR spectrum (DMSO-d ₆ ) δppm:
2.12 (3H, s), 3.27 (2H, t, J = 5.
1 Hz), 4.45 (2H, t, J = 5.1 Hz),
7.63 (2H, d, J = 8.6 Hz), 7.75 (2
H, d, J = 8.6 Hz), 8.23 (3H, br)
s).

Example 25 3- (2-Aminoethoxy) -5- (4-chlorophenyl) -4-ethylisoxazole hydrochloride (Exemplary Compound No .: 149) (a) 3- (2- (N-tercia) Libutoxycarbonylamino) ethoxy) -5- (4-chlorophenyl)
-4-Ethylisoxazole Example 14 was prepared using 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl) isoxazole (0.4 g) and ethyl iodide (0.11 ml). The target compound (0.26 g, 61%) was obtained as a colorless oil by reacting in the same manner as in (a) and performing post-treatment. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 34
60, 2980, 1713; NMR spectrum (CDCl ₃ ) δ ppm: 1.2
0 (3H, t, J = 7.4 Hz), 1.46 (9H,
s), 2.54 (2H, q, J = 7.4 Hz), 3.5
9 (2H, q, J = 5.2 Hz), 4.37 (2H,
t, J = 5.2 Hz), 4.90 (1H, brs),
7.45 (2H, d, J = 8.5 Hz), 7.59 (2
H, d, J = 8.5 Hz).

(B) 3- (2-aminoethoxy) -5
-(4-Chlorophenyl) -4-ethylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl) -4-ethylisoxazole (0.22 g ) Was reacted in the same manner as in Example 9 (b) and worked up to give the target compound (0.13 g, 72%) as colorless crystals. Melting point: 217-220 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 297
2,2892,1515; NMR spectrum (DMSO-d ₆ ) δ ppm:
1.14 (3H, t, J = 7.5 Hz), 2.58 (2
H, q, J = 7.5 Hz), 3.28 (2H, t, J =
5.2 Hz), 4.46 (2H, t, J = 5.2H)
z), 7.64 (2H, d, J = 8.6 Hz), 7.7
1 (2H, d, J = 8.6 Hz), 8.20 (3H, b
rs).

Example 26 3- (2-Aminoethoxy) -5- (4-chlorophenyl) -4-propylisoxazole hydrochloride (Exemplary Compound No .: 150) (a) 3- (2- (N-tercia) Libutoxycarbonylamino) ethoxy) -5- (4-chlorophenyl)
-4-Propylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl) isoxazole (0.4 g) and propyl iodide (0.14 ml)
Was reacted in the same manner as in Example 14 (a) and worked up to give the target compound (0.21 g, 47%) as a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 339
2,2963, 1685; NMR spectrum (CDCl ₃ ) δ ppm: 0.9
6 (3H, t, J = 7.4 Hz), 1.46 (9H,
s), 1.57-1.69 (2H, m), 2.49 (2
H, t, J = 7.6 Hz), 3.58 (2H, q, J =
5.2 Hz), 4.37 (2H, t, J = 5.2H)
z), 4.87 (1H, brs), 7.45 (2H,
d, J = 8.6 Hz), 7.60 (2H, d, J = 8.
6 Hz).

(B) 3- (2-aminoethoxy) -5
-(4-Chlorophenyl) -4-propylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl) -4-propylisoxazole (0.19 g ) In Example 9 (b).
By subjecting to post-treatment, the target compound (0.13 g, 81%) was obtained as colorless crystals. Melting point: 146-149 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 295
8,2871,2829,1516; NMR Spectrum (DMSO-d ₆₎ δppm:
0.90 (3H, t, J = 7.3 Hz), 1.50-
1.59 (2H, m), 2.54 (2H, t, J = 7.
3 Hz), 3.28 (2H, t, J = 5.2 Hz),
4.45 (2H, t, J = 5.2 Hz), 7.63 (2
H, d, J = 8.7 Hz), 7.72 (2H, d, J =
8.7 Hz), 8.21 (3H, brs).

Example 27 3- (2-Aminoethoxy) -5- (4-methylphenyl) isoxazole hydrochloride (Exemplary Compound No .: 26
0) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-methylphenyl)
Example 9 Isoxazole 3-hydroxy-5- (4-methylphenyl) isoxazole (1.5 g) and 2- (N-tert-butoxycarbonylamino) ethanol (1.5 g) were used.
The target compound (2.2 g, 82%) was obtained as a colorless powder by reacting and treating in the same manner as in (a). IR spectrum (KBr) ν _max cm ^-1 : 337
5,3356,3332,1719,1684; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 2.40 (3H, s), 3.56 (2
H, q, J = 5.1 Hz), 4.35 (2H, t, J =
5.1Hz), 4.94 (1H, brs), 6.09
(1H, s), 7.26 (2H, d, J = 8.1H
z), 7.61 (2H, d, J = 8.1 Hz).

(B) 3- (2-aminoethoxy) -5
-(4-Methylphenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-methylphenyl) isoxazole (0.3 g) was the same as in Example 9 (b). The target compound (0.16 g,
67%) as colorless crystals. Melting point: 215-220 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 299
3,2979,1622; NMR spectrum (DMSO-d ₆ ) δ ppm:
2.37 (3H, s), 3.25 (2H, t, J = 5.
0 Hz), 4.44 (2H, t, J = 5.0 Hz),
6.76 (1H, s), 7.35 (2H, d, J = 8.
1 Hz), 7.74 (2H, d, J = 8.1 Hz),
8.26 (3H, brs).

Example 28 3- (2-Aminoethoxy) -5- (4-trifluoromethylphenyl) isoxazole hydrochloride (Exemplary Compound No .: 332) (a) 3- (2- (N-tert-butoxycarbonyl) Amino) ethoxy) -5- (4-trifluoromethylphenyl) isoxazole 3-hydroxy-5- (4-trifluoromethylphenyl) isoxazole (0.2 g) and 2- (N-tert-butoxycarbonylamino) ethanol ( 0.15
g) was reacted in the same manner as in Example 9 (a) and worked up to give the target compound (0.26 g, 81%) as a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 337
6,1679,1608; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.58 (2H, q, J = 5.1H)
z), 4.37 (2H, t, J = 5.1 Hz), 4.9
2 (1H, brs), 6.25 (1H, s), 7.72
(2H, d, J = 8.2 Hz), 7.84 (2H, d,
J = 8.2 Hz).

(B) 3- (2-aminoethoxy) -5
-(4-trifluoromethylphenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-trifluoromethylphenyl) isoxazole (0.24 g) was prepared in Example 9 ( The target compound (0.14 g, 70%) was obtained as colorless crystals by carrying out the same reaction as in b) and post-treatment. Melting point: 226-232 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 299
3,2965,2914,1608; NMR spectrum (DMSO-d ₆ ) δppm:
3.27 (2H, t, J = 5.1 Hz), 4.47 (2
H, t, J = 5.1 Hz), 7.07 (1H, s),
7.93 (2H, d, J = 8.3 Hz), 8.09 (2
H, d, J = 8.3 Hz), 8.26 (3H, br)
s).

Example 29 3- (2-Aminoethoxy) -5- (4-fluorophenyl) isoxazole hydrochloride (Exemplary Compound No .: 6
6) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-fluorophenyl) isoxazole 5- (4-fluorophenyl) -3-hydroxyisoxazole (0.06 g) ) Was reacted with 2- (N-tert-butoxycarbonylamino) ethanol (0.06 g) in the same manner as in Example 9 (a), followed by post-treatment to give the target compound (0.08 g, 74%) as a colorless product. As a powder. IR spectrum (KBr) ν _max cm ^-1 : 337
5,1682; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.56 (2H, q, J = 5.1H
z), 4.35 (2H, t, J = 5.1 Hz), 4.9
3 (1H, brs), 6.09 (1H, s), 7.15
(2H, t, J = 8.6 Hz), 7.71 (2H, d
d, J = 8.6 Hz, J = 5.3 Hz).

(B) 3- (2-aminoethoxy) -5
-(4-Fluorophenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-fluorophenyl) isoxazole (0.05 g) was used in the same manner as in Example 9 (b). And post-treatment to give the target compound (0.02
g, 56%) as colorless crystals. Melting point: 232-238 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 299
3,2978,2911,1621; NMR spectrum (DMSO-d ₆ ) δppm:
3.26 (2H, t, J = 5.0 Hz), 4.44 (2
H, t, J = 5.0 Hz), 6.84 (1H, s),
7.40 (2H, t, J = 8.8 Hz), 7.93 (2
H, dd, J = 8.8 Hz, J = 5.3 Hz), 8.2
5 (3H, brs).

Example 30 3- (2-Aminoethoxy) -5- (1-naphthyl) isoxazole hydrochloride (exemplified compound number: 475) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy ) -5- (1-Naphthyl) isoxazole Example 9 was prepared using 3-hydroxy-5- (1-naphthyl) isoxazole (0.20 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.17 g).
The target compound (0.30 g, 89%) was obtained as a colorless powder by reacting and post-treating in the same manner as in (a). IR spectrum (KBr) ν _max cm ^-1 : 331
8,1712; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
7 (9H, s), 3.61 (2H, q, J = 5.3H
z), 4.42 (2H, t, J = 5.3 Hz), 4.9
7 (1H, brs), 6.25 (1H, s), 7.52
−7.61 (3H, m), 7.77-7.79 (1H,
m), 7.90-7.99 (2H, m), 8.27-
8.31 (1H, m).

(B) 3- (2-aminoethoxy) -5
-(1-Naphthyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (1-naphthyl) isoxazole (0.28 g) was reacted in the same manner as in Example 9 (b). Then, by post-treatment, the target compound (0.18 g, 78
%) As colorless crystals. Melting point: 201-205 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 300
2,2968,2913,1602; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.31 (2H, t, J = 5.1 Hz), 4.52 (2
H, t, J = 5.1 Hz), 6.83 (1H, s),
7.63-7.70 (3H, m), 7.87-7.89
(1H, m), 8.07-8.25 (3H, m), 8.
30 (3H, brs).

Example 31 3- (2-Aminoethoxy) -4-bromo-5-phenylisoxazole hydrochloride (Exemplary compound number: 135
7) (a) 4-bromo-3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole 4-bromo-3-hydroxy-5-phenylisoxazole (0.2 g) ) And 2- (N-tert-butoxycarbonylamino) ethanol (0.15 g) in Example 9
The target compound (0.26 g, 81%) was obtained as a colorless powder by performing the same reaction as in (a) and performing post-treatment. IR spectrum (KBr) ν _max cm ^-1 : 335
2,2976, 1719, 1709; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
7 (9H, s), 3.61 (2H, q, J = 5.1H
z), 4.41 (2H, t, J = 5.1 Hz), 4.9
7 (1H, brs), 7.47-7.55 (3H,
m), 7.98-8.04 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Bromo-5-phenylisoxazole hydrochloride 4-bromo-3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.24 g) was prepared in Example 9 (b). The target compound (0.13 g,
(65%) as colorless crystals. Melting point: 192-198 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 299
1,291,2894,1614,1594,157
4; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.32 (2H, t, J = 5.1 Hz), 4.54 (2
H, t, J = 5.1 Hz), 7.60-7.66 (3
H, m), 7.95-7.98 (2H, m), 8.19
(3H, brs). Example 32 3- (2-Aminoethoxy) -4-iodo-5-phenylisoxazole hydrochloride (Exemplary compound number: 135
9) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-iodo-5-phenylisoxazole 3-hydroxy-4-iodo-5-phenylisoxazole (0.2 g) ) And 2- (N-tert-butoxycarbonylamino) ethanol (0.12 g) in Example 9
The target compound (0.22 g, 73%) was obtained as a colorless powder by performing the same reaction as in (a) and performing post-treatment. IR spectrum (KBr) ν _max cm ^-1 : 332
8,2977,1696; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
7 (9H, s), 3.61 (2H, q, J = 5.2H
z), 4.41 (2H, t, J = 5.2 Hz), 4.9
7 (1H, brs), 7.47-7.55 (3H,
m), 7.99-8.06 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Iodo-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-iodo-5-phenylisoxazole (0.20 g) in Example 9 (b) The target compound (0.12 g,
71%) as colorless crystals. Melting point: 201-206 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 296
1,921,1591; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.30 (2H, t, J = 5.3 Hz), 4.51 (2
H, t, J = 5.3 Hz), 7.58-7.64 (3
H, m), 7.96-8.01 (2H, m), 8.22
(3H, brs). Example 33 3- (2-aminoethoxy) -5- (4-isopropylphenyl) isoxazole hydrochloride (exemplified compound number: 1618) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy)- 5- (4-isopropylphenyl) isoxazole 3-hydroxy-5- (4-isopropylphenyl) isoxazole (0.2 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.17 g) were prepared in Example 9 ( The target compound (0.26 g, 77%) was obtained as a colorless powder by carrying out the same reaction as in a) and post-treatment. IR spectrum (KBr) ν _max cm ^-1 : 332
6,2973,1713,1697,1623; NMR spectrum (CDCl ₃ ) δ ppm: 1.2
7 (6H, d, J = 6.9 Hz), 1.46 (9H,
s), 2.95 (1H, qq, J = 6.9 Hz, J =
6.9 Hz), 3.56 (2H, q, J = 5.1H)
z), 4.35 (2H, t, J = 5.1 Hz), 4.9
4 (1H, brs), 6.09 (1H, s), 7.31
(2H, d, J = 8.3 Hz), 7.65 (2H, d,
J = 8.3 Hz).

(B) 3- (2-aminoethoxy) -5
-(4-Isopropylphenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-isopropylphenyl) isoxazole (0.25 g) as in Example 9 (b) And post-treatment to give the target compound (0.1
1 g, 55%) as colorless crystals. Melting point: 162-166 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 300
0, 2959, 2924, 1623, 1604; NMR spectrum (DMSO-d ₆ ) δ ppm:
1.23 (6H, d, J = 6.9 Hz), 2.96 (1
H, qq, J = 6.9 Hz, J = 6.9 Hz), 3.2
6 (2H, t, J = 5.1 Hz), 4.44 (2H,
t, J = 5.1 Hz), 6.77 (1H, s), 7.4
1 (2H, d, J = 8.2 Hz), 7.77 (2H,
d, J = 8.2 Hz), 8.20 (3H, brs).

Example 34 3- (2-Aminoethoxy) -5- (2-methylphenyl) isoxazole hydrochloride (Exemplary Compound No .: 22
4) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-methylphenyl)
Example 9 isoxazole 3-hydroxy-5- (2-methylphenyl) isoxazole (0.2 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.2 g) were used.
The target compound (0.31 g, 86%) was obtained as a colorless powder by performing the same reaction as in (a) and performing post-treatment. IR spectrum (KBr) ν _max cm ^-1 : 331
5,1710,1619; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 2.49 (3H, s), 3.57 (2
H, q, J = 5.2 Hz), 4.37 (2H, t, J =
5.2Hz), 4.95 (1H, brs), 6.06
(1H, s), 7.19-7.39 (3H, m), 7.
65-7.69 (1H, m).

(B) 3- (2-aminoethoxy) -5
-(2-Methylphenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-methylphenyl) isoxazole (0.30 g) as in Example 9 (b) The target compound (0.18 g,
75%) as colorless crystals. Melting point: 165-167 ° C; IR spectrum (KBr) ν _max cm ^-1 : 299
6,2976,2911,1613; NMR Spectrum (DMSO-d ₆₎ δppm:
2.46 (3H, s), 3.26 (2H, t, J = 5.
2 Hz), 4.46 (2H, t, J = 5.2 Hz),
6.59 (1H, s), 7.34-7.46 (3H,
m), 7.67-7.69 (1H, m), 8.21 (3
H, brs).

Example 35 3- (2-Aminoethoxy) -5- (4-phenylphenyl) isoxazole hydrochloride (Exemplary Compound No .: 36
8) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-phenylphenyl) isoxazole 3-hydroxy-5- (4-phenylphenyl) isoxazole (0.2 g) By reacting 2- (N-tert-butoxycarbonylamino) ethanol (0.15 g) in the same manner as in Example 9 (a) and performing post-treatment,
The target compound (0.22 g, 69%) was obtained as a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 334
5,1694; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.58 (2H, q, J = 5.1H)
z), 4.37 (2H, t, J = 5.1 Hz), 4.9
5 (1H, brs), 6.18 (1H, s), 7.37
-7.51 (3H, m), 7.61-7.70 (4H,
m), 7.79-7.82 (2H, m). (B) 3- (2-aminoethoxy) -5- (4-phenylphenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-phenylphenyl) isoxazole ( 0.2g) was reacted in the same manner as in Example 9 (b) and worked up to give the desired compound (0.1g, 6
3%) as colorless crystals. Melting point: 212-218 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 299
6,2966,2909,1619,1602; NMR Spectrum (DMSO-d ₆₎ δppm:
3.27 (2H, t, J = 5.1 Hz), 4.46 (2
H, t, J = 5.1 Hz), 6.90 (1H, s),
7.41-7.55 (3H, m), 7.74-7.76
(2H, m), 7.84-7.87 (2H, m), 7.
94-7.96 (2H, m), 8.18 (3H, br
s).

Example 36 3- (2-Aminoethoxy) -5- (4-phenoxyphenyl) isoxazole hydrochloride (exemplary compound number:
1632) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-phenoxyphenyl) isoxazole 3-hydroxy-5- (4-phenoxyphenyl) isoxazole (0.2 g) 2- (N-tert-butoxycarbonylamino) ethanol (0.14 g) was reacted in the same manner as in Example 9 (a) and post-treated to give the target compound (0.23 g, 74%) as a colorless powder As obtained. IR spectrum (KBr) ν _max cm ^-1 : 333
1,1720; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.56 (2H, q, J = 5.2H
z), 4.34 (2H, t, J = 5.2 Hz), 4.9
5 (1H, brs), 6.06 (1H, s), 7.02
−7.08 (4H, m), 7.15-7.20 (1H,
m), 7.35-7.42 (2H, m), 7.65-
7.70 (2H, m).

(B) 3- (2-aminoethoxy) -5
-(4-Phenoxyphenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-phenoxyphenyl) isoxazole (0.18 g) as in Example 9 (b) And post-treatment to give the target compound (0.1
g, 67%) as colorless crystals. Melting point: 207-213 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 300
0,2959,2909,1625; NMR spectrum (DMSO-d ₆ ) δppm:
3.26 (2H, t, J = 5.1 Hz), 4.43 (2
H, t, J = 5.1 Hz), 6.76 (1H, s),
7.10-7.14 (4H, m), 7.21-7.25
(1H, m), 7.44-7.48 (2H, m), 7.
85-7.88 (2H, m), 8.18 (3H, br
s).

Example 37 3- (2-Aminoethoxy) -5- (2-trifluoromethylphenyl) isoxazole hydrochloride (Exemplary Compound No .: 296) (a) 3- (2- (N-tert-butoxycarbonyl) Amino) ethoxy) -5- (2-trifluoromethylphenyl) isoxazole 3-hydroxy-5- (2-trifluoromethylphenyl) isoxazole (0.3 g) and 2- (N-tert-butoxycarbonylamino) ethanol ( 0.23
g) was reacted in the same manner as in Example 9 (a) and worked up to give the desired compound (0.36 g, 74%) as a colorless oil. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 34
57, 2983, 1712; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.58 (2H, q, J = 5.2H
z), 4.37 (2H, t, J = 5.2 Hz), 4.9
6 (1H, brs), 6.21 (1H, s), 7.56
−7.69 (2H, m), 7.75-7.82 (2H,
m).

(B) 3- (2-aminoethoxy) -5
-(2-trifluoromethylphenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-trifluoromethylphenyl) isoxazole (0.35 g) was prepared in Example 9 ( The target compound (0.22 g, 76%) was obtained as colorless crystals by carrying out the same reaction as in b) and post-treatment. Melting point: 118-122 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 299
6,2917,1622; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.28 (2H, t, J = 5.1 Hz), 4.46 (2
H, t, J = 5.1 Hz), 6.63 (1H, s),
7.79-7.89 (3H, m), 7.96-7.98
(1H, m), 8.22 (3H, brs).

Example 38 3- (2-Aminoethoxy) -5- (4-hydroxyphenyl) isoxazole hydrochloride (Exemplary compound number:
1674) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-hydroxyphenyl) isoxazole 3-hydroxy-5- (4-hydroxyphenyl) isoxazole (0.1 g) 2- (N-tert-butoxycarbonylamino) ethanol (0.1 g) was reacted in the same manner as in Example 9 (a) and post-treated to give
The target compound (0.12 g, 67%) was obtained as a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 333
1,3247,1698,1666,1645,161
9; NMR spectrum (DMSO-d ₆ ) δ ppm:
1.38 (9H, s), 3.32 (2H, q, J = 5.
6 Hz), 4.17 (2H, t, J = 5.6 Hz),
6.53 (1H, s), 6.87 (2H, d, J = 8.
8 Hz), 7.05 (1H, brs), 7.63 (2
H, d, J = 8.8 Hz), 8.98 (1H, br)
s).

(B) 3- (2-aminoethoxy) -5
-(4-Hydroxyphenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-hydroxyphenyl) isoxazole (0.12 g) as in Example 9 (b) The target compound (0.05
g, 56%) as colorless crystals. Melting point: 240-245 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 314
5,305,1620; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.24 (2H, t, J = 5.1 Hz), 4.41 (2
H, t, J = 5.1 Hz), 6.58 (1H, s),
6.90 (2H, d, J = 8.7 Hz), 7.67 (2
H, d, J = 8.7 Hz), 8.13 (3H, br)
s).

Example 39 3- (2-Aminoethoxy) -5- (2,4-dichlorophenyl) isoxazole hydrochloride (Exemplary Compound No .: 170) (a) 3- (2- (N-tert-butoxycarbonylamino) ) Ethoxy) -5- (2,4-dichlorophenyl) isoxazole 5- (2,4-dichlorophenyl) -3-hydroxyisoxazole (0.2 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0 .17g) was reacted in the same manner as in Example 9 (a) and worked up to give the target compound (0.26 g, 81%) as a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 338
6,1681,1606; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.57 (2H, q, J = 5.2H
z), 4.37 (2H, t, J = 5.2 Hz), 4.9
4 (1H, brs), 6.58 (1H, s), 7.38
(1H, dd, J = 8.5 Hz, J = 2.1 Hz),
7.53 (1H, d, J = 2.1 Hz), 7.85 (1
H, d, J = 8.5 Hz).

(B) 3- (2-aminoethoxy) -5
-(2,4-Dichlorophenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-dichlorophenyl) isoxazole (0.24 g) was prepared in Example 9 (b). The target compound (0.1
2g, 60%) as colorless crystals. Melting point: 192-195 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 306
9,3005,2967,1611; NMR Spectrum (DMSO-d ₆₎ δppm:
3.27 (2H, t, J = 5.1 Hz), 4.47 (2
H, t, J = 5.1 Hz), 6.84 (1H, s),
7.64 (1H, dd, J = 8.7 Hz, J = 2.1H
z), 7.89 (1H, d, J = 2.1 Hz), 7.9
0 (1H, d, J = 8.7 Hz), 8.20 (3H, b
rs).

Example 40 3- (2-Aminoethoxy) -5- (3,4-dichlorophenyl) isoxazole hydrochloride (Exemplary Compound No .: 1604) (a) 3- (2- (N-tert-butoxycarbonylamino) ) Ethoxy) -5- (3,4-dichlorophenyl) isoxazole 5- (3,4-dichlorophenyl) -3-hydroxyisoxazole (0.3 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0 .23g) was reacted in the same manner as in Example 9 (a) and worked up to give the target compound (0.41 g, 85%) as a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 336
9,1687; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.56 (2H, q, J = 5.1H
z), 4.35 (2H, t, J = 5.1 Hz), 4.9
1 (1H, brs), 6.16 (1H, s), 7.54
(2H, s), 7.80 (1H, s).

(B) 3- (2-aminoethoxy) -5
-(3,4-Dichlorophenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (3,4-dichlorophenyl) isoxazole (0.4 g) was prepared in Example 9 (b). And post-treatment to give the target compound (0.22
g, 67%) as colorless crystals. Melting point: 202-210 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 299
3,2977,2915,1617; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.26 (2H, t, J = 5.1 Hz), 4.45 (2
H, t, J = 5.1 Hz), 7.02 (1H, s),
7.84 (1H, d, J = 8.9 Hz), 7.85 (1
H, d, J = 8.9 Hz), 8.17 (4H, br)
s).

Example 41 3- (2-Aminoethoxy) -5- (2,3-dichlorophenyl) isoxazole hydrochloride (Exemplary Compound No .: 1526) (a) 3- (2- (N-tert-butoxycarbonylamino) ) Ethoxy) -5- (2,3-dichlorophenyl) isoxazole 5- (2,3-dichlorophenyl) -3-hydroxyisoxazole (0.3 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0 .23g) was reacted in the same manner as in Example 9 (a) and worked up to give the target compound (0.37 g, 77%) as a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 338
1,1688,1607; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.58 (2H, q, J = 5.1H)
z), 4.37 (2H, t, J = 5.1 Hz), 4.9
5 (1H, brs), 6.60 (1H, s), 7.34
(1H, t, J = 7.9 Hz), 7.58 (1H, d
d, J = 7.9 Hz, J = 1.4 Hz), 7.81 (1
H, dd, J = 7.9 Hz, J = 1.4 Hz).

(B) 3- (2-aminoethoxy) -5
-(2,3-Dichlorophenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,3-dichlorophenyl) isoxazole (0.36 g) was prepared in Example 9 (b). The target compound (0.2
(0 g, 67%) as colorless crystals. Melting point: 183-186 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 301
0, 2979, 2908, 1604; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.27 (2H, t, J = 5.1 Hz), 4.48 (2
H, t, J = 5.1 Hz), 6.87 (1H, s),
7.57 (1H, t, J = 7.8 Hz), 7.82-
7.87 (2H, m), 8.19 (3H, brs).

Example 42 3- (2-Aminoethoxy) -5- (2,6-dichlorophenyl) isoxazole hydrochloride (Exemplary Compound No .: 188) (a) 3- (2- (N-tert-butoxycarbonylamino) ) Ethoxy) -5- (2,6-dichlorophenyl) isoxazole 5- (2,6-dichlorophenyl) -3-hydroxyisoxazole (0.3 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0 .23g) was reacted in the same manner as in Example 9 (a) and worked up to give the target compound (0.31 g, 65%) as a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 335
8, 1703, 1626; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.58 (2H, q, J = 5.1H)
z), 4.39 (2H, t, J = 5.1 Hz), 4.9
6 (1H, brs), 6.11 (1H, s), 7.32
-7.44 (3H, m).

(B) 3- (2-aminoethoxy) -5
-(2,6-Dichlorophenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,6-dichlorophenyl) isoxazole (0.16 g) was prepared in Example 9 (b). And post-treatment to give the target compound (0.0
7 g, 54%) as colorless crystals. Melting point: 148-151 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 300
5,2966,2935,1631; NMR Spectrum (DMSO-d ₆₎ δppm:
3.27 (2H, t, J = 5.0 Hz), 4.47 (2
H, t, J = 5.0 Hz), 6.69 (1H, s),
7.61-7.71 (3H, m), 8.15 (3H, b
rs).

Example 43 3- (2-Aminoethoxy) -5- (2,4-difluorophenyl) isoxazole hydrochloride (Exemplary Compound No. 93) (a) 3- (2- (N-tert-butoxycarbonyl) Amino) ethoxy) -5- (2,4-difluorophenyl) isoxazole 5- (2,4-difluorophenyl) -3-hydroxyisoxazole (0.3 g) and 2- (N-tert-butoxycarbonylamino) Ethanol (0.27g)
Was reacted in the same manner as in Example 9 (a), and post-treated to give the target compound (0.44 g, 85%) as a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 338
2,1694; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.57 (2H, q, J = 5.1H
z), 4.36 (2H, t, J = 5.1 Hz), 4.9
3 (1H, brs), 6.30 (1H, s), 6.90
−7.05 (2H, m), 7.85-7.94 (1H,
m).

(B) 3- (2-aminoethoxy) -5
-(2,4-difluorophenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-difluorophenyl)
Isoxazole (0.42 g) was reacted in the same manner as in Example 9 (b) and post-treated to give the target compound (0.4 g).
32g, 94%) as colorless crystals. Melting point: 226-232 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 299
7, 2980, 2922, 1626; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.26 (2H, t, J = 5.1 Hz), 4.47 (2
H, t, J = 5.1 Hz), 6.63 (1H, s),
7.29-7.34 (1H, m), 7.53-7.59
(1H, m), 7.94-8.00 (1H, m), 8.
21 (3H, brs).

Example 44 3- (2-Aminoethoxy) -4- (1-chloroethyl) -5-phenylisoxazole hydrochloride (Exemplary Compound No .: 1390) (a) 3- (2- (N-tercia) L-butoxycarbonylamino) ethoxy) -4- (1-hydroxyethyl) -5-phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.8
g) was dissolved in tetrahydrofuran (16 ml), butyllithium (1.6 M hexane solution, 3.7 ml) was added dropwise at -70 ° C under a nitrogen atmosphere, and the mixture was stirred for 10 minutes. After dropping acetaldehyde (0.22 ml),
After stirring for 10 minutes and raising the temperature to 0 ° C., the reaction solution was poured into ice water, and the pH of the solution was adjusted using an aqueous solution of potassium phosphate.
Was adjusted to 6. After extraction with ethyl acetate, the organic layer was washed with saturated saline, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent:
Purification using hexane / ethyl acetate = 2/1) gave the target compound (0.90 g, 98%) as a colorless oil. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 36
02, 3459, 2982, 2936, 1712; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
5 (9H, s), 1.60 (3H, d, J = 6.7H
z), 2.64 (1H, brs), 3.58 (2H,
q, J = 5.0 Hz), 4.39 (2H, t, J = 5.
0 Hz), 4.90-5.10 (2H, m), 7.45
−7.50 (3H, m), 7.64-7.69 (2H,
m).

(B) 3- (2-aminoethoxy) -4
-(1-chloroethyl) -5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (1-hydroxyethyl) -5-
Phenylisoxazole (0.2 g) was prepared in Example 1 (b).
By subjecting to post-treatment, the target compound (0.13 g, 75%) was obtained as colorless crystals. Melting point: 200-204 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 297
5,1640; NMR spectrum (DMSO-d ₆ ) δ ppm:
1.86 (3H, d, J = 7.0 Hz), 3.27 (2
H, t, J = 5.2 Hz), 4.52 (2H, t, J =
5.2Hz), 5.46 (1H, q, J = 7.0H)
z), 7.60-7.68 (3H, m), 7.71-
7.77 (2H, m), 8.20 (3H, brs).

Example 45 4-Acetyl-3- (2-aminoethoxy) -5-phenylisoxazole hydrochloride (Exemplary Compound No .: 141)
0) (a) 4-acetyl-3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4 -(1-hydroxyethyl) -5-
Phenylisoxazole (0.3 g) was dissolved in methylene chloride (3 ml), pyridium dichromate (0.49 g) was added at room temperature, and the mixture was stirred at the same temperature for 24 hours.
After completion of the reaction, insolubles were removed by filtration, and the solvent was distilled off under reduced pressure. The compound (0.26 g, 87%) was obtained as a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 335
9,1685; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
7 (9H, s), 2.51 (3H, s), 3.65 (2
H, q, J = 5.2 Hz), 4.48 (2H, t, J =
5.2Hz), 4.87 (1H, brs), 7.40-
7.63 (3H, m), 7.93-7.96 (2H,
m).

(B) 4-acetyl-3- (2-aminoethoxy) -5-phenylisoxazole hydrochloride 4-acetyl-3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- By reacting phenylisoxazole (0.2 g) in the same manner as in Example 9 (b) and performing post-treatment, the target compound (0.12 g,
75%) as colorless crystals. Melting point: 150-152 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 300
6,2909,1682; NMR spectrum (DMSO-d ₆ ) δ ppm:
2.52 (3H, s), 3.35 (2H, t, J = 5.
0 Hz), 4.59 (2H, t, J = 5.0 Hz),
7.54-7.64 (3H, m), 7.85-7.88
(2H, m), 8.30 (3H, brs).

Example 46 3- (2-aminoethoxy) -4-isopropenyl-5
-Phenylisoxazole hydrochloride (Exemplary compound No .: 1394) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy-4- (1-hydroxyisopropyl) -5-phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.8
g) was dissolved in tetrahydrofuran (16 ml), butyllithium (1.6 M hexane solution, 3.7 ml) was added dropwise at -70 ° C under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 10 minutes. Then, acetone (0.3 ml) was added dropwise,
After stirring for 10 minutes, the temperature was raised to 0 ° C. The reaction solution was poured into ice water, and the solution was added using an aqueous solution of potassium phosphate.
After adjusting the H to 6, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated saline, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (elution solvent: hexane / acetic acid). Purification using ethyl (3/1) gave the target compound (0.42 g, 44%) as a colorless oil. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 34
60, 2982, 2936, 1713; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 1.50 (6H, s), 2.52 (1
H, brs), 3.60 (2H, q, J = 5.3H)
z), 4.41 (2H, t, J = 5.3 Hz), 4.8
7 (1H, brs), 7.41-7.49 (3H,
m), 7.52-7.56 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Isopropenyl-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy-4- (1-hydroxyisopropyl)-
5-phenylisoxazole (0.13 g) was dissolved in 4N hydrochloric acid / 1,4-dioxane solution (10 ml),
The mixture was stirred at 100 ° C. for 1 hour. After completion of the reaction, the reaction solution was allowed to cool, the solvent was distilled off under reduced pressure, and the obtained residue was washed with ethyl acetate to give the target compound (0.10).
g, 83%) as colorless crystals. Melting point: 130-133 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 297
4,1591,1572; NMR spectrum (DMSO-d ₆ ) δ ppm:
1.95 (3H, s), 3.28 (2H, t, J = 5.
2 Hz), 4.48 (2H, t, J = 5.2 Hz),
5.23 (1H, s), 5.33 (1H, s), 7.5
3-7.58 (3H, m), 7.62-7.71 (2
H, m), 8.20 (3H, brs).

Example 47 3- (2-Aminoethoxy) -5- (4-nitrophenyl) isoxazole hydrochloride (Exemplary Compound No .: 166)
0) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy-5- (4-nitrophenyl) isoxazole 3-hydroxy-5- (4-nitrophenyl) isoxazole (0.64 g) and 2 -(N-tert-butoxycarbonylamino) ethanol (0.55 g) was reacted in the same manner as in Example 9 (a),
The target compound (0.86 g, 80%) was obtained as a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 338
5,1681; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.57 (2H, q, J = 5.2H
z), 4.38 (2H, t, J = 5.2 Hz), 4.9
0 (1H, brs), 6.33 (1H, s), 7.90
(2H, d, J = 8.6 Hz), 8.33 (2H, d,
J = 8.6 Hz).

(B) 3- (2-aminoethoxy) -5
-(4-Nitrophenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy-5- (4-nitrophenyl) isoxazole (0.28 g) was prepared in the same manner as in Example 9 (b). The target compound (0.12 g,
52%) as colorless crystals. Melting point: 216-220 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 299
4,2977,2913,1620,1608; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.28 (2H, t, J = 5.1 Hz), 4.47 (2
H, t, J = 5.1 Hz), 7.16 (1H, s),
8.15 (2H, d, J = 8.9 Hz), 8.22 (3
H, brs), 8.39 (2H, d, J = 8.9H)
z).

Example 48 3- (2-Aminoethoxy) -5- (4-aminophenyl) isoxazole dihydrochloride (Exemplary Compound No .: 17
02) (a) 5- (4-aminophenyl) -3- (2- (N
-Tert-butoxycarbonylamino) ethoxy)
Isoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-nitrophenyl) isoxazole (0.55 g) was mixed with a mixed solvent of acetic acid and water (9:
1,5.5 ml) and zinc powder (0.5 ml) at room temperature.
After adding 5 g), the mixture was stirred at the same temperature for 2 hours. After completion of the reaction, the zinc dust was removed by filtration, and the filtrate was extracted with ethyl acetate.
The organic layer was washed with saturated saline and dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/1) to give the desired compound (0.45 g, 90%).
%) As a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 339
1,3378,3300,1712,1615; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.55 (2H, q, J = 5.1H
z), 4.00 (2H, brs), 4.33 (2H,
t, J = 5.1 Hz), 4.96 (1H, brs),
5.94 (1H, s), 6.70 (2H, d, J = 8.
7 Hz), 7.52 (2H, d, J = 8.7 Hz).

(B) 3- (2-aminoethoxy) -5
-(4-Aminophenyl) isoxazole dihydrochloride 5- (4-aminophenyl) -3- (2- (N-tert-butoxycarbonylamino) ethoxy) isoxazole (0.25 g) was prepared according to Example 9 (b). The target compound (0.15 g,
(65%) as colorless crystals. Melting point: 242-248 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 303
9,2939,2584,1625,1597; NMR Spectrum (DMSO-d ₆₎ δppm:
3.25 (2H, t, J = 5.0 Hz), 4.21 (2
H, brs), 4.42 (2H, t, J = 5.0H)
z), 6.56 (1H, s), 6.94 (2H, d, J
= 8.3 Hz), 7.65 (2H, d, J = 8.3H)
z), 8.25 (3H, brs).

Example 49 3- (2-Aminoethoxy) -5- (4-benzoylaminophenyl) isoxazole hydrochloride (Exemplary Compound No .: 1716) (a) 5- (4-benzoylaminophenyl) -3-
(2- (N-tert-butoxycarbonylamino)
Ethoxy) isoxazole 5- (4-aminophenyl) -3- (2- (N-tert-butoxycarbonylamino) ethoxy) isoxazole (0.1 g) was dissolved in tetrahydrofuran (1 ml) and heated to 5 ° C. under a nitrogen atmosphere. Triethylamine (0.05 ml) and then benzoyl chloride (0.
04 ml) was added dropwise and stirred at room temperature for 30 minutes. The reaction solution was poured into ice water, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure,
The obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/1) to give the desired compound (0.08 g, 62
%) As a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 337
5,1712; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.57 (2H, q, J = 5.1H
z), 4.35 (2H, t, J = 5.1 Hz), 4.9
6 (1H, brs), 6.12 (1H, s), 7.52
−7.61 (3H, m), 7.72-7.80 (4H,
m), 7.87-7.95 (3H, m). (B) 3- (2-aminoethoxy) -5- (4-benzoylaminophenyl) isoxazole hydrochloride 5- (4-benzoylaminophenyl) -3- (2-
(N-tert-butoxycarbonylamino) ethoxy) isoxazole (0.07 g) was reacted in the same manner as in Example 9 (b) and post-treated to give the target compound (0.04 g, 68%) as colorless crystals. As obtained. Melting point: 242-248 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 332
2,2959,2910,1645,1621; NMR spectrum (DMSO-d ₆ ) δppm:
3.26 (2H, t, J = 5.1 Hz), 4.44 (2
H, t, J = 5.1 Hz), 6.75 (1H, s),
7.53-7.65 (3H, m), 7.83-8.00
(6H, m), 8.20 (3H, brs), 10.55
(1H, s).

Example 50 3- (2-Aminoethoxy) -5- (2,4-dichloro-3-methylphenyl) isoxazole hydrochloride (Exemplary Compound No .: 1576) (a) 3- (2- (N- Tert-butoxycarbonylamino) ethoxy) -5- (2,4-dichloro-3
-Methylphenyl) isoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-dichlorophenyl) isoxazole (0.3 g) and methyl iodide (0.08 m
1) was reacted in the same manner as in Example 14 (a) and worked up to give the target compound (0.14 g, 45%) as a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 334
2,1710; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 2.56 (3H, s), 3.58 (2
H, q, J = 5.1 Hz), 4.38 (2H, t, J =
5.1 Hz), 4.95 (1H, brs), 6.54
(1H, s), 7.39 (1H, d, J = 8.5H
z), 7.76 (1H, d, J = 8.5 Hz).

(B) 3- (2-aminoethoxy) -5
-(2,4-dichloro-3-methylphenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-dichloro-3-methylphenyl) isoxazole (0 .13g) in Example 9.
The target compound (0.06 g, 55%) was obtained as colorless crystals by carrying out the same reaction as in (b) and post-treatment. Melting point: 197-200 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 313
0,2969,2897,1607; NMR spectrum (DMSO-d ₆ ) δppm:
2.52 (3H, s), 3.27 (2H, t, J = 5.
1 Hz), 4.47 (2H, t, J = 5.1 Hz),
6.82 (1H, s), 7.65 (1H, d, J = 8.
5 Hz), 7.71 (1H, d, J = 8.5 Hz),
8.17 (3H, brs).

Example 51 3- (2-Aminoethoxy) -5- (2,4-dichloro-3-ethylphenyl) isoxazole hydrochloride (Exemplary Compound No .: 1590) (a) 3- (2- (N- Tert-butoxycarbonylamino) ethoxy) -5- (2,4-dichloro-3
-Ethylphenyl) isoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-dichlorophenyl) isoxazole (0.3 g) and ethyl iodide (0.1 m
l) was reacted in the same manner as in Example 14 (a) and worked up to give the target compound (0.25 g, 78%) as a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 334
2,1702; NMR spectrum (CDCl ₃ ) δ ppm: 1.2
1 (3H, t, J = 7.5 Hz), 1.46 (9H,
s), 3.05 (2H, q, J = 7.5 Hz), 3.5
7 (2H, q, J = 5.1 Hz), 4.36 (2H,
t, J = 5.1 Hz), 4.94 (1H, brs),
6.54 (1H, s), 7.40 (1H, d, J = 8.
5 Hz), 7.65 (1 H, d, J = 8.5 Hz).

(B) 3- (2-aminoethoxy) -5
-(2,4-Dichloro-3-ethylphenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-dichloro-3-ethylphenyl) isoxazole (0 .23 g) in Example 9.
The target compound (0.14 g, 74%) was obtained as colorless crystals by carrying out the same reaction as in (b) and post-treatment. Melting point: 173-176 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 297
0,2935,2876,1608; NMR spectrum (DMSO-d ₆ ) δ ppm:
1.16 (3H, t, J = 7.4 Hz), 3.00 (2
H, q, J = 7.4 Hz), 3.27 (2H, t, J =
5.1 Hz), 4.47 (2H, t, J = 5.1H)
z), 6.82 (1H, s), 7.65 (1H, d, J
= 8.4 Hz), 7.70 (1H, d, J = 8.4H)
z), 8.21 (3H, brs).

Example 52 5- (4-acetoxyphenyl) -3- (2-aminoethoxy) isoxazole hydrochloride (exemplary compound number:
1688) (a) 5- (4-acetoxyphenyl) -3- (2-
(N-tert-butoxycarbonylamino) ethoxy) isoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-hydroxyphenyl) isoxazole (0.15 g) was added to tetrahydrofuran (1.
5 ml), triethylamine (0.07 ml) and then acetyl chloride (0.
04 ml) was added dropwise and stirred at room temperature for 30 minutes. The reaction solution was poured into ice water, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/1) to give the desired compound (0.12 g, 71 %) As a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 334
5,1696; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 2.33 (3H, s), 3.56 (2
H, q, J = 5.2 Hz), 4.35 (2H, t, J =
5.2Hz), 4.94 (1H, brs), 6.12
(1H, s), 7.20 (2H, d, J = 8.8H
z), 7.74 (2H, d, J = 8.8 Hz).

(B) 5- (4-acetoxyphenyl)
-3- (2-Aminoethoxy) isoxazole hydrochloride 5- (4-acetoxyphenyl) -3- (2- (N-tert-butoxycarbonylamino) ethoxy) isoxazole (0.1 g) was prepared in Example 9 (b). And post-treatment to give the desired compound (0.05
g, 63%) as colorless crystals. Melting point: 202-212 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 299
6,2977,2912,1755,1621; NMR Spectrum (DMSO-d ₆₎ δppm:
2.30 (3H, s), 3.26 (2H, t, J = 5.
1 Hz), 4.45 (2H, t, J = 5.1 Hz),
6.84 (1H, s), 7.32 (2H, d, J = 8.
6 Hz), 7.91 (2H, d, J = 8.6 Hz),
8.22 (3H, brs).

Example 53 3- (2-Aminoethoxy) -5- (4-benzyloxyphenyl) isoxazole hydrochloride (Exemplary Compound No .: 1646) (a) 5- (4-benzyloxyphenyl) -3-
(2- (N-tert-butoxycarbonylamino)
Ethoxy) isoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-hydroxyphenyl) isoxazole (0.2 g) was added to dimethylformamide (2 m
l), 55% sodium hydride (oil-based, 0.03 g) was added at 5 ° C under a nitrogen atmosphere.
Stirred for minutes. Then, benzyl bromide (0.08 ml) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into ice water, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/1) to give a residue.
The target compound (0.14 g, 54%) was obtained as a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 333
8,1698; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.56 (2H, q, J = 5.0H
z), 4.34 (2H, t, J = 5.0 Hz), 4.9
4 (1H, brs), 5.12 (2H, s), 6.02
(1H, s), 7.04 (2H, d, J = 8.7H)
z), 7.28-7.47 (5H, m), 7.66 (2
H, d, J = 8.7 Hz).

(B) 3- (2-aminoethoxy) -5
-(4-benzyloxyphenyl) isoxazole hydrochloride 5- (4-benzyloxyphenyl) -3- (2- (N
-Tert-butoxycarbonylamino) ethoxy)
Isoxazole (0.13 g) was reacted in the same manner as in Example 9 (b), and post-treated to give the target compound (0.1 g).
07g, 64%) as colorless crystals. Melting point: 205-210 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 299
7, 2966, 2912, 1621, 1604; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.25 (2H, t, J = 5.1 Hz), 4.43 (2
H, t, J = 5.1 Hz), 5.19 (2H, s),
6.69 (1H, s), 7.17 (2H, d, J = 9.
0 Hz), 7.33-7.48 (5H, m), 7.79
(2H, d, J = 9.0 Hz), 8.21 (3H, br
s).

Example 54 3- (2-aminoethoxy) -5- (2-furyl) -4
-Isopropylisoxazole hydrochloride (Exemplary compound number: 510) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-furyl) -4-isopropylisoxazole 5- (2-furyl) -3-hydroxy-4-isopropylisoxazole (0.2 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.18
g) was reacted in the same manner as in Example 9 (a) and worked up to give the target compound (0.29 g, 83%) as a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 331
7, 2985, 1690; NMR spectrum (CDCl ₃ ) δ ppm: 1.2
8 (6H, d, J = 7.2 Hz), 1.46 (9H,
s), 3.33 (1H, qq, J = 7.2 Hz, J =
7.2 Hz), 3.58 (2H, q, J = 5.1H)
z), 4.35 (2H, t, J = 5.1 Hz), 4.8
4 (1H, brs), 6.52 (1H, dd, J = 3.
4 Hz, J = 1.8 Hz), 6.80 (1H, d, J =
3.4 Hz), 7.55 (1H, d, J = 1.8H)
z).

(B) 3- (2-aminoethoxy) -5
-(2-furyl) -4-isopropylisoxazole
Hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-furyl) -4-isopropylisoxazole (0.27 g) was reacted in the same manner as in Example 1 (b). After that, the target compound (0.17 g, 77%) was obtained as colorless crystals. Melting point: 137-139 ° C; IR spectrum (KBr) ν _max cm ^-1 : 297
2,2898,1560,1513; NMR spectrum (DMSO-d ₆ ) δ ppm:
1.26 (6H, d, J = 7.0 Hz), 3.24 (1
H, qq, J = 7.0 Hz, J = 7.0 Hz), 3.2
8 (2H, t, J = 5.2 Hz), 4.44 (2H,
t, J = 5.2 Hz), 6.73 (1H, dd, J =
3.4 Hz, J = 1.8 Hz), 7.01 (1H, d,
J = 3.4 Hz), 7.97 (1H, d, J = 1.8H)
z), 8.21 (3H, brs).

Example 55 3- (2-Aminoethoxy) -4- (tert-butyl) -5-phenylisoxazole hydrochloride (Exemplary Compound No .: 13) (a) 3- (2- (N-tert-butyl) Leaveoxycarbonylamino) ethoxy) -4- (tert-butyl)
-5-phenylisoxazole 4- (tert-butyl) -3-hydroxy-5-phenylisoxazole (0.15 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.
12g) was reacted in the same manner as in Example 9 (a) and worked up to give the target compound (0.16 g, 64%) as a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 337
4,2974,1683; NMR spectrum (CDCl ₃ ) δ ppm: 1.1
8 (9H, s), 1.46 (9H, s), 3.60 (2
H, q, J = 5.2 Hz), 4.38 (2H, t, J =
5.2Hz), 4.85 (1H, brs), 7.36-
7.55 (5H, m).

(B) 3- (2-aminoethoxy) -4
-(Tert-butyl) -5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (tert-butyl) -5-phenylisoxazole (0.14 g) ) In Example 1 (b)
By subjecting to post-treatment, the target compound (0.09 g, 82%) was obtained as colorless crystals. Melting point: 230-234 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 296
1,910,2890,1516; NMR spectrum (DMSO-d ₆ ) δppm:
1.16 (9H, s), 3.30 (2H, t, J = 5.
3 Hz), 4.46 (2H, t, J = 5.3 Hz),
7.44-7.57 (5H, m), 8.20 (3H, b
rs).

Example 56 3- (2-aminoethoxy) -4-cyclopropyl-5
-Phenylisoxazole hydrochloride (Exemplary compound number: 1400) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-cyclopropyl-5-phenylisoxazole 4-cyclopropyl- 3-hydroxy-5-phenylisoxazole (0.2 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.18 g) were reacted in the same manner as in Example 9 (a) and worked up. As a result, the target compound (0.25 g, 74%) was obtained as a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 336
9,1692,1536,1520; NMR spectrum (CDCl ₃ ) δ ppm: 0.6
6-0.75 (2H, m), 0.88-0.95 (2
H, m), 1.46 (9H, s), 1.67-1.73.
(1H, m), 3.58 (2H, q, J = 5.1H
z), 4.35 (2H, t, J = 5.1 Hz), 4.9
0 (1H, brs), 7.40-7.51 (3H,
m), 7.84-7.87 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Cyclopropyl-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-cyclopropyl-5-phenylisoxazole (0.15 g) was prepared in Example 1 ( The reaction was carried out in the same manner as in b), and the target compound (0.0
(6 g, 49%) as colorless crystals. Melting point: 180-182 ° C; IR spectrum (KBr) ν _max cm ^-1 : 291
9,2851,1713,1519; NMR Spectrum (DMSO-d ₆₎ δppm:
0.68-0.76 (2H, m), 0.83-0.92
(2H, m), 1.71-1.78 (1H, m), 3.
27 (2H, t, J = 5.2 Hz), 4.44 (2H,
t, J = 5.2 Hz), 7.51-7.60 (3H,
m), 7.83-7.86 (2H, m), 8.20 (3
H, brs).

Example 57 3- (2-Aminoethoxy) -5- (2,4-dichlorophenyl) -4-isopropylisoxazole hydrochloride (Exemplary Compound No .: 176) (a) 3- (2- (N -Tert-butoxycarbonylamino) ethoxy) -5- (2,4-dichlorophenyl) -4-isopropylisoxazole 5- (2,4
-Dichlorophenyl) -3-hydroxy-4-isopropylisoxazole (0.06 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.0
4g) was reacted in the same manner as in Example 9 (a) and worked up to give the target compound (0.078 g, 86%) as a colorless oil. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 34
60, 2975, 2936, 1713; NMR spectrum (CDCl ₃ ) δ ppm: 1.1
8 (6H, d, J = 7.0 Hz), 1.46 (9H,
s), 2.69 (1H, qq, J = 7.0 Hz, J =
7.0Hz), 3.59 (2H, q, J = 5.2H)
z), 4.38 (2H, t, J = 5.2 Hz), 4.8
5 (1H, brs), 7.30 (1H, d, J = 8.3)
Hz), 7.35 (1H, dd, J = 8.3 Hz, J =
1.9 Hz), 7.52 (1H, d, J = 1.9H)
z).

(B) 3- (2-aminoethoxy) -5
-(2,4-dichlorophenyl) -4-isopropylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-dichlorophenyl)-
By reacting 4-isopropylisoxazole (0.07 g) in the same manner as in Example 1 (b) and performing post-treatment,
The target compound (0.04 g, 68%) was obtained as colorless crystals. Melting point: 171-173 ° C; IR spectrum (KBr) ν _max cm ^-1 : 296
8, 2934, 2875, 1514; NMR spectrum (DMSO-d ₆ ) δ ppm:
1.13 (6H, d, J = 7.0 Hz), 2.69 (1
H, qq, J = 7.0 Hz, J = 7.0 Hz), 3.2
9 (2H, t, J = 5.3 Hz), 4.46 (2H,
t, J = 5.3 Hz), 7.56 (1H, d, J = 8.
5Hz), 7.62 (1H, dd, J = 8.5Hz, J
= 2.0 Hz), 7.89 (1H, d, J = 2.0H)
z), 8.18 (3H, brs).

Example 58 3- (2-Aminoethoxy) -5- (2-chlorophenyl) -4-isopropylisoxazole hydrochloride (Exemplary Compound No. 117) (a) 3- (2- (N-tert-a) Libutoxycarbonylamino) ethoxy) -5- (2-chlorophenyl)
4-isopropylisoxazole 5- (2-chlorophenyl) -3-hydroxy-4-isopropylisoxazole (0.13 g) and 2- (N-
By reacting tert-butoxycarbonylamino) ethanol (0.1 g) in the same manner as in Example 9 (a) and performing post-treatment, the target compound (0.15 g, 72%) was obtained.
Was obtained as a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 338
2,2974,1691; NMR spectrum (CDCl ₃ ) δ ppm: 1.1
8 (6H, d, J = 6.9 Hz), 1.46 (9H,
s), 2.71 (1H, qq, J = 6.9 Hz, J =
6.9 Hz), 3.60 (2H, q, J = 5.2H)
z), 4.39 (2H, t, J = 5.2 Hz), 4.8
7 (1H, brs), 7.34-7.51 (4H,
m).

(B) 3- (2-aminoethoxy) -5
-(2-chlorophenyl) -4-isopropylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-chlorophenyl) -4-isopropylisoxazole (0.13 g ) In Example 1
The target compound (0.08 g, 73%) was obtained as colorless crystals by carrying out the same reaction as in (b) and post-treatment. Melting point: 143-145 ° C; IR spectrum (KBr) ν _max cm ^-1 : 297
0,2937,2896,2879,1513; NMR Spectrum (DMSO-d ₆₎ δppm:
1.13 (6H, d, J = 7.0 Hz), 2.69 (1
H, qq, J = 7.0 Hz, J = 7.0 Hz), 3.2
9 (2H, t, J = 5.2 Hz), 4.47 (2H,
t, J = 5.2 Hz), 7.50-7.68 (4H,
m), 8.24 (3H, brs).

Example 59 3- (2-Aminoethoxy) -5- (4-chlorophenyl) -4-isopropylisoxazole hydrochloride (Exemplary Compound No .: 151) (a) 3- (2- (N-tercia) Libutoxycarbonylamino) ethoxy) -5- (4-chlorophenyl)
4-Isopropylisoxazole 5- (4-chlorophenyl) -3-hydroxy-4-isopropylisoxazole (0.15 g) and 2- (N-
Tertiary butoxycarbonylamino) ethanol (0.11 g) was reacted in the same manner as in Example 9 (a) and post-treated to give the target compound (0.19 g, 79
%) As a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 338
2,2966,1685; NMR spectrum (CDCl ₃ ) δ ppm: 1.2
9 (6H, d, J = 7.0 Hz), 1.46 (9H,
s), 3.03 (1H, qq, J = 7.0 Hz, J =
7.0 Hz), 3.59 (2H, q, J = 5.1H)
z), 4.36 (2H, t, J = 5.1 Hz), 7.4
4 (2H, d, J = 8.7 Hz), 7.52 (2H,
d, J = 8.7 Hz).

(B) 3- (2-aminoethoxy) -5
-(4-Chlorophenyl) -4-isopropylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl) -4-isopropylisoxazole (0.18 g ) In Example 1
The target compound (0.12 g, 80%) was obtained as colorless crystals by carrying out the same reaction as in (b) and post-treatment. Melting point: 224-227 ° C; IR spectrum (KBr) ν _max cm ^-1 : 297
1,919,2851,1639; NMR spectrum (DMSO-d ₆ ) δppm:
1.26 (6H, d, J = 7.0 Hz), 3.02 (1
H, qq, J = 7.0 Hz, J = 7.0 Hz), 3.2
8 (2H, t, J = 5.3 Hz), 4.45 (2H,
t, J = 5.3 Hz), 7.62 (2H, d, J = 9.
0 Hz), 7.63 (2H, d, J = 9.0 Hz),
8.18 (3H, brs).

Example 60 4-allyl-3- (2-aminoethoxy) -5-phenylisoxazole hydrochloride (Exemplary Compound No .: 139)
2) (a) 4-allyl-3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole 4-allyl-3-hydroxy-5-phenylisoxazole (1.00 g) ) And 2- (N-tert-butoxycarbonylamino) ethanol (0.96 g) were reacted in the same manner as in Example 1 (a),
The target compound (1.57 g, 91%) was obtained as colorless crystals. Melting point: 78-79 ° C; IR spectrum (KBr) ν _max cm ^-1 : 332
7, 1708, 1644, 1526, 1518; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.27-3.29 (2H, m),
3.57 (2H, q, J = 5.1 Hz), 4.38 (2
H, t, J = 5.1 Hz), 4.90 (1H, br)
s), 5.05-5.15 (2H, m), 5.91-
6.01 (1H, m), 7.41-7.49 (3H,
m), 7.63-7.68 (2H, m).

(B) 4-allyl-3- (2-aminoethoxy) -5-phenylisoxazole hydrochloride 4-allyl-3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- Phenylisoxazole (200 mg) was reacted in the same manner as in Example 1 (b) and worked up to give the target compound (160 mg,
98%) as colorless crystals. Melting point: 95-96 ° C; IR spectrum (KBr) ν _max cm ^-1 : 296
7, 2912, 2885, 2817, 2694, 164
3,1601, 1577, 1514, 1495; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.25-3.30 (2H, m), 3.35 (2H,
t, J = 5.1 Hz), 4.46 (2H, t, J = 5.
1 Hz), 5.03-5.09 (2H, m), 5.91
−6.00 (1H, m), 7.52-7.58 (3H,
m), 7.67-7.70 (2H, m), 8.20 (3
H, brs).

Example 61 3- (2-Aminoethoxy) -5-phenyl-4-propargylisoxazole hydrochloride (Exemplary compound number:
1398) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenyl-4-propargyl isoxazole 3-hydroxy-5-phenyl-4-propargyl isoxazole (1.00 g) ) Was reacted with 2- (N-tert-butoxycarbonylamino) ethanol (0.96 g) in the same manner as in Example 1 (a), followed by post-treatment to give the target compound (1.44 g, 84%) as a colorless product. As an oil. IR spectrum (KBr) ν _max cm ^-1 : 335
2,3302,1711,1643,1600,157
7,1520,1499; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 2.09 (1H, t, J = 2.8H)
z), 3.43 (2H, d, J = 2.8 Hz), 3.6
0 (2H, q, J = 5.1 Hz), 4.41 (2H,
t, J = 5.1 Hz), 5.02 (1H, brs),
7.45-7.55 (3H, m), 7.74-7.76
(2H, m).

(B) 3- (2-aminoethoxy) -5
-Phenyl-4-propargyl isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenyl-4-propargyl isoxazole (200 mg) as in Example 1 (b) To the target compound (152 m
g, 94%) as colorless crystals. Melting point: 210-212 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 325
8,2959,2899,2830,1632,160
1,1577,1523; NMR spectrum (DMSO-d ₆ ) δ ppm:
2.97 (1H, t, J = 2.8 Hz), 3.30 (1
H, t, J = 5.1 Hz), 3.59 (2H, d, J =
2.8 Hz), 4.47 (2H, t, J = 5.1H)
z), 7.56-7.62 (3H, m), 7.79-
7.82 (2H, m), 8.13 (3H, brs).

Example 62 3- (2-Aminoethoxy) -4-isobutyl-5-phenylisoxazole hydrochloride (Exemplary Compound No .: 1)
1) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isobutyl-5-phenylisoxazole 3-hydroxy-4-isobutyl-5-phenylisoxazole (217 mg) 2- (N-tert-butoxycarbonylamino) ethanol (193 mg) was reacted in the same manner as in Example 1 (a), and post-treated to give the target compound (303 mg, 84%) as colorless crystals. Melting point: 80-81 ° C; IR spectrum (KBr) ν _max cm ^-1 : 337
7, 1683, 1637, 1516, 1498; NMR spectrum (CDCl ₃ ) δ ppm: 0.9
3 (6H, d, J = 6.8 Hz), 1.46 (9H,
s), 1.89-1.96 (1H, m), 2.42 (2
H, d, J = 7.3 Hz), 3.58 (2H, q, J =
5.1 Hz), 4.37 (2H, t, J = 5.1H)
z), 4.88 (1H, brs), 7.40-7.49
(3H, m), 7.66-7.70 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Isobutyl-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isobutyl-5-phenylisoxazole (200 mg) as in Example 1 (b) The target compound (160 m
g, 98%) as colorless crystals. Melting point: 202-210 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 300
5,2957,2869,1629,1601,157
6,1514,1495; NMR spectrum (DMSO-d ₆ ) δ ppm:
0.86 (6H, d, J = 6.8 Hz), 2.47 (2
H, d, J = 7.3 Hz), 3.27 (2H, t, J =
5.1 Hz), 4.45 (2H, t, J = 5.1H)
z), 7.49-7.58 (3H, m), 7.70-
7.74 (2H, m), 8.19 (3H, brs).

Example 63 3- (2-Aminoethoxy) -4-cyclopentyl-5
-Phenylisoxazole hydrochloride (Exemplary compound number: 1402) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-cyclopentyl-5-phenylisoxazole 3-hydroxy-4- Cyclopentyl-5-phenylisoxazole (229 mg) and 2- (N-tert-butoxycarbonylamino) ethanol (193 mg)
Was reacted in the same manner as in Example 1 (a) and worked up to give the target compound (308 mg, 83%) as colorless crystals. Melting point: 112-113 ° C; IR spectrum (KBr) ν _max cm ^-1 : 339
1,1691,1655,1643,1531,151
5; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 1.56-1.67 (2H, m),
1.71-1.92 (6H, m), 3.03-3.12
(1H, m), 3.58 (2H, q, J = 5.1H
z), 4.38 (2H, t, J = 5.1 Hz), 4.8
2 (1H, brs), 7.41-7.49 (3H,
m), 7.55-7.61 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Cyclopentyl-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-cyclopentyl-5-phenylisoxazole (200 mg) as in Example 1 (b) And post-treatment to give the target compound (161
mg, 97%) as colorless crystals. Melting point: 197-199 ° C; IR spectrum (KBr) ν _max cm ^-1 : 295
4,2869,1637,1599,1576,151
1,1490; NMR spectrum (DMSO-d ₆ ) δ ppm:
1.57-1.63 (2H, m), 1.72-1.91
(6H, m), 2.98-3.07 (1H, m), 3.
27 (2H, t, J = 5.1 Hz), 4.45 (2H,
t, J = 5.1 Hz), 7.51-7.61 (5H,
m), 8.07 (3H, brs).

Example 64 3- (2-Aminoethoxy) -4- (2-cyclopentenyl) -5-phenylisoxazole hydrochloride (Exemplary Compound No .: 1404) (a) 3- (2- (N- Tert-butoxycarbonylamino) ethoxy) -4- (2-cyclopentenyl) -5-phenylisoxazole 3-hydroxy-4- (2-cyclopentenyl) -5
Phenylisoxazole (227 mg) and 2- (N-tert-butoxycarbonylamino) ethanol (1
93 mg) was reacted in the same manner as in Example 1 (a) and worked up to give the target compound (295 mg, 80%).
Was obtained as colorless crystals. Melting point: 81-82 ° C; IR spectrum (KBr) ν _max cm ^-1 : 339
4,1690,1636,1515,1495; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 1.88-1.98 (1H, m),
2.24-2.34 (1H, m), 2.39-2.49
(1H, m), 2.52-2.61 (1H, m), 3.
47-3.59 (2H, m), 4.01-4.06 (1
H, m), 4.30-4.36 (2H, m), 4.86
(1H, brs), 5.63-5.67 (1H, m),
5.89-5.92 (1H, m), 7.42-7.49
(3H, m), 7.60-7.63 (2H, m).

(B) 3- (2-aminoethoxy) -4
-(2-cyclopentenyl) -5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (2-cyclopentenyl) -5-
Example 1 with phenylisoxazole (200 mg)
The target compound (156 mg, 94%) was obtained as colorless crystals by carrying out the same reaction as in (b) and post-treatment. Melting point: 157-160 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 305
1,954, 2901, 2852, 1635, 159
9, 1575, 1516, 1492; NMR spectrum (DMSO-d ₆ ) δ ppm:
1.79-1.99 (1H, m), 2.21-2.41
(2H, m), 2.44-2.53 (1H, m), 3.
25 (2H, brs), 3.95-4.02 (1H,
m), 4.38-4.48 (2H, m), 5.56-
5.71 (1H, m), 5.85-5.89 (1H,
m), 7.51-7.57 (3H, m), 7.59-
7.63 (2H, m), 8.12 (3H, brs).

Example 65 3- (2-Aminoethoxy) -4-pentyl-5-phenylisoxazole hydrochloride (Exemplified Compound No .: 138
6) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-pentyl-5-phenylisoxazole 3-hydroxy-4-pentyl-5-phenylisoxazole (231 mg) 2- (N-tert-butoxycarbonylamino) ethanol (193 mg) was reacted in the same manner as in Example 1 (a), and post-treated to give
The desired compound (305 mg, 82%) was obtained as a colorless oily substance. IR spectrum (KBr) ν _max cm ^-1 : 346
1,1713,1640,1510,1496; NMR spectrum (CDCl ₃ ) δ ppm: 0.8
9 (3H, t, J = 7.0 Hz), 1.26-1.38
(2H, m), 1.46 (9H, s), 1.49-1.
61 (2H, m), 2.52 (2H, t, J = 7.7H
z), 3.59 (2H, q, J = 5.1 Hz), 4.3
7 (2H, t, J = 5.1 Hz), 4.89 (1H, b
rs), 7.40-7.49 (3H, m), 7.64-
7.69 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Pentyl-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-pentyl-5-phenylisoxazole (100 mg) as in Example 1 (b) The target compound (80 mg, 9
5%) as colorless crystals. Melting point: 107-109 ° C; IR spectrum (KBr) ν _max cm ^-1 : 300
8, 2955, 2930, 2869, 1641, 160
1,1576,1566,1516,1496; NMR Spectrum (DMSO-d ₆₎ δppm:
0.83 (3H, t, J = 7.0 Hz), 1.25-
1.30 (4H, m), 1.48-1.56 (2H,
m), 2.55 (2H, t, J = 7.7 Hz), 3.2
8 (2H, t, J = 5.1 Hz), 4.45 (2H,
t, J = 5.1 Hz), 7.51-7.59 (3H,
m), 7.66-7.69 (2H, m), 8.10 (3
H, brs).

Example 66 3- (2-aminoethoxy) -4- (2-butenyl)-
5-phenylisoxazole hydrochloride (Exemplary compound number: 1396) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (2-butenyl) -5-
Phenylisoxazole 3-hydroxy-4- (2-butenyl) -5-phenylisoxazole (215 mg)
And 2- (N-tert-butoxycarbonylamino)
Ethanol (193 mg) was reacted in the same manner as in Example 1 (a) and post-treated to give the target compound (292 m
g, 82%) as colorless crystals. Melting point: 62-63 ° C; IR spectrum (KBr) ν _max cm ^-1 : 337
8, 1682, 1634, 1514, 1497; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 1.68-1.74 (3H, m),
3.19-3.21 (2H, m), 3.57 (2H,
q, J = 5.1 Hz), 4.37 (2H, t, J = 5.
1 Hz), 4.89 (1H, brs), 5.46-5.
60 (2H, m), 7.40-7.52 (3H, m),
7.64-7.68 (2H, m).

(B) 3- (2-aminoethoxy) -4
-(2-butenyl) -5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (2-butenyl) -5-phenylisoxazole (200 mg) The target compound (16) was reacted and post-treated in the same manner as in Example 1 (b).
2 mg, 98%) as colorless crystals. Melting point: 123-125 ° C; IR spectrum (KBr) ν _max cm ^-1 : 302
8,2961,2934,2916,2855,164
1,1601,1577,1570,1515,149
4; NMR spectrum (DMSO-d ₆ ) δ ppm:
1.60-1.70 (3H, m), 3.26-3.28
(2H, m), 3.33 (2H, t, J = 5.1H
z), 4.45 (2H, t, J = 5.1 Hz), 5.4
3-5.59 (2H, m), 7.50-7.58 (3
H, m), 7.65-7.70 (2H, m), 8.10
(3H, brs).

Example 67 3- (2-aminoethoxy) -4-isopropyl-5
(2-thienyl) isoxazole hydrochloride (Exemplary Compound No .: 543) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isopropyl-5- (2
-Thienyl) isoxazole 3-hydroxy-4-isopropyl-5- (2-thienyl) isoxazole (209 mg) and 2- (N-tert-butoxycarbonylamino) ethanol (193)
mg) was reacted in the same manner as in Example 1 (a) and worked up to give the target compound (301 mg, 86%) as colorless crystals. Melting point: 94-95 ° C; IR spectrum (KBr) ν _max cm ^-1 : 332
5,1711,1693,1635,1542,152
8,1508; NMR spectrum (CDCl ₃ ) δ ppm: 1.2
9 (6H, d, J = 7.1 Hz), 1.46 (9H,
s), 3.19 (1H, m), 3.58 (2H, q, J
= 5.1 Hz), 4.36 (2H, t, J = 5.1H)
z), 4.83 (1H, brs), 7.14 (1H, d
d, J = 5.3 Hz, J = 3.7 Hz), 7.42 (1
H, dd, J = 3.4 Hz, J = 1.4 Hz), 7.4
6 (1H, d, J = 5.3 Hz).

(B) 3- (2-aminoethoxy) -4
-Isopropyl-5- (2-thienyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isopropyl-5- (2-thienyl) isoxazole (200 mg) was prepared in Example 1 ( The target compound (150 mg, 93%) was obtained as colorless crystals by performing the same reaction as in b) and performing post-treatment. Melting point: 192-194 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 310
5,3087,2973,1644,1579,152
7,1498; NMR spectrum (DMSO-d ₆ ) δ ppm:
1.27 (6H, d, J = 7.2 Hz), 3.16 (1
H, m), 3.28 (2H, t, J = 5.1 Hz),
4.44 (2H, t, J = 5.1 Hz), 7.26 (1
H, dd, J = 5.2 Hz, J = 1.4 Hz), 7.5
4 (1H, dd, J = 4.7 Hz, J = 1.0 Hz),
7.87 (1H, d, J = 5.2 Hz), 8.13 (3
H, brs).

Example 68 3- (2-Aminoethoxy) -4-fluoro-5-phenylisoxazole hydrochloride (Exemplary Compound No .: 4) (a) 3-Methoxymethoxy-5-phenylisoxazole 3- Hydroxy-5-phenylisoxazole (8.0
5 g) was dissolved in dimethylformamide (80 ml), and sodium methoxide (28% methanol solution,
After adding 3.24 g), the mixture was stirred at room temperature for 1 hour. The reaction solution was cooled to 5 ° C., and chloromethyl methyl ether (4.
83 g) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was poured into ice water (200 ml) and extracted with ether (200 ml).
x2), and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4/1) to give the desired compound (6.30 g, 61). %) As a colorless oil. IR spectrum (KBr) ν _max cm ^-1 : 162
1,1596,1577,1512; NMR spectrum (CDCl ₃ ) δ ppm: 3.5
8 (3H, s), 5.37 (2H, s), 7.40-
7.48 (3H, m), 7.71-7.95 (2H,
m).

(B) 4-Fluoro-3-methoxymethoxy-5-phenylisoxazole 3-methoxymethoxy-5-phenylisoxazole (2.05 g) was dissolved in anhydrous tetrahydrafuran (30 ml). 78 ° C
Then, butyllithium (1.68 M hexane solution, 7.1 ml) was added dropwise, and the mixture was stirred at the same temperature for 15 minutes. Next, N-fluorodibenzenesulfonimide (3.15 g) was added, and the mixture was stirred at the same temperature for 15 minutes. Then, the cooling bath was removed, and the temperature was raised to room temperature. The reaction solution was added to ice water (2
00ml) and extracted with ether (200mlx
2) was performed, and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to give the desired compound (1.78 g, 80%). %) As a colorless oil. IR spectrum (KBr) ν _max cm ^-1 : 167
2,1545; NMR spectrum (CDCl ₃ ) δ ppm: 3.6
2 (3H, s), 5.45 (2H, s), 7.43-
7.52 (3H, m), 7.70-7.80 (2H,
m).

(C) 4-fluoro-3-hydroxy-
5-Phenylisoxazole 4-Fluoro-3-methoxymethoxy-5-phenylisoxazole (0.44 g) was dissolved in a 4N hydrochloric acid / dioxane solution (5.0 ml) and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained crystals were washed with dichloromethane (10 ml) to obtain the desired compound (0.30 g, 83%) as colorless crystals. IR spectrum (KBr) ν _max cm ^-1 : 305
9,3014,2995,2919,2851,282
2,2747,2645,2565,1674,158
2,1527; NMR spectrum (DMSO-d ₆ ) δ ppm:
7.51-7.61 (3H, m), 7.73-7.74
(2H, m), 12.6 (1H, brs).

(D) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-fluoro-
5-Phenylisoxazole 4-Fluoro-3-hydroxy-5-phenylisoxazole (100 mg) and 2- (N-tert-butoxycarbonylamino) ethanol (108 mg) were reacted in the same manner as in Example 1 (a). And by post-processing,
The target compound (132 mg, 73%) was obtained as colorless crystals. Melting point: 103-104 ° C; IR spectrum (KBr) ν _max cm ^-1 : 332
5,1718,1667,1549,1532; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.60 (2H, q, J = 5.1H
z), 4.41 (2H, t, J = 5.1 Hz), 4.9
7 (1H, brs), 7.41-7.52 (3H,
m), 7.76-7.79 (2H, m).

(E) 3- (2-aminoethoxy) -4
-Fluoro-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-fluoro-5-phenylisoxazole (110 mg) as in Example 1 (b) The target compound (82 mg, 9
3%) as colorless crystals. Melting point: 207-211 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 299
9,2965,2909,2845,1665,160
2,1581,1555,1532; NMR Spectrum (DMSO-d ₆₎ δppm:
3.32 (2H, t, J = 5.1 Hz), 4.55 (2
H, t, J = 5.1 Hz), 7.55-7.64 (3
H, m), 7.75-7.78 (2H, m), 8.17.
(3H, brs).

Example 69 3- (2-Dimethylaminoethoxy) -5-phenylisoxazole hydrochloride (Exemplified Compound No. 27) (a) 3- (2-Bromoethoxy) -5-phenylisoxazole tri Phenylphosphine (15.7 g) was dissolved in toluene (200 ml), cooled to 5 ° C., diethyl azodicarboxylate (10.4 g) was added, and the mixture was stirred at the same temperature for 10 minutes. Next, 3-hydroxy-5-phenylisoxazole (8.0 g) and 2-bromoethanol (7.5 g) were added in that order, and the same temperature was maintained for 10 minutes.
The mixture was further stirred at room temperature for 2 hours. After filtering off the insoluble matter, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4).
/ 1) to give the desired compound (12.1).
g, 90%) as colorless crystals. IR spectrum (KBr) ν _max cm ^-1 : 314
8, 1623, 1597, 1576, 1510; NMR spectrum (CDCl ₃ ) δ ppm: 3.7
1 (2H, t, J = 5.9 Hz), 4.62 (2H,
t, J = 5.9 Hz), 6.19 (1H, s), 7.4
2-7.49 (3H, m), 7.70-7.77 (2
H, m).

(B) 3- (2-Dimethylaminoethoxy) -5-phenylisoxazoledimethylamine hydrochloride (815 mg) was dissolved in methanol (50 ml), and then dissolved in 3- (2-bromoethoxy) -5. -Phenylisoxazole (268 mg) and triethylamine (2.
8 ml) and heated under reflux for 8 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was washed with ether (20 m
1), washed with diluted saline (20 ml),
The organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent is distilled off under reduced pressure, and the obtained residue is purified by silica gel column chromatography (elution solvent: ethyl acetate) to give the desired compound (146).
mg, 63%) as colorless crystals. Melting point: 28-29 ° C; IR spectrum (KBr) ν _max cm ^-1 : 298
0,2951,1625,1597,1577,151
4; NMR spectrum (CDCl ₃ ) δ ppm: 2.3
4 (6H, s), 2.75 (2H, t, J = 5.4H
z), 4.40 (2H, t, J = 5.4 Hz), 6.1
8 (1H, s), 7.40-7.48 (3H, m),
7.69-7.73 (2H, m).

(C) 3- (2-Dimethylaminoethoxy) -5-phenylisoxazole hydrochloride 3- (2-Dimethylaminoethoxy) -5-phenylisoxazole (130 mg) was added to dioxane (1.0 m
l) and dissolved in 4N hydrochloric acid / dioxane solution (0.2
ml) was added and left at room temperature for 15 minutes. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with ethyl acetate (5 ml) to give the desired compound (148 mg, 98%).
Was obtained as colorless crystals. Melting point: 163-164 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 313
3,1624,1597,1577,1513; NMR spectrum (DMSO-d ₆ ) δ ppm:
2.84 (6H, s), 3.55 (2H, t, J = 5.
0 Hz), 4.61 (2H, t, J = 5.0 Hz),
7.50-7.58 (3H, m), 7.81-7.87
(2H, m), 10.31 (1H, brs).

Example 70 5-Phenyl-3- (2- (1-piperidyl) ethoxy) isoxazole hydrochloride (Exemplary Compound No. 28) (a) 5-Phenyl-3- (2- (1-piperidyl))
(Ethoxy) isoxazole 3- (2-bromoethoxy) -5-phenylisoxazole (268 mg) was dissolved in methanol (1.0 ml), and piperidine (426 mg) was added, followed by heating under reflux for 3 hours. After adding the reaction solution to ice water (20 ml),
Ether extraction (20 ml × 2) was performed, and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain the desired compound (251 mg, 92%) as colorless crystals. Was. Melting point: 75-76 ° C; IR spectrum (KBr) ν _max cm ^-1 : 314
9, 1625, 1598, 1577, 1513; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
2-1.48 (2H, m), 1.54-1.67 (4
H, m), 2.50 (4H, brs), 2.79 (2
H, t, J = 5.8 Hz), 4.42 (2H, t, J =
5.8 Hz), 6.16 (1 H, s), 7.41-7.
48 (3H, m), 7.69-7.75 (2H, m).

(B) 5-phenyl-3- (2- (1-
The target compound (181 m
g, 80%) as colorless crystals. Melting point: 190-192 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 295
0,2938,1620,1595,1576,151
1; NMR spectrum (DMSO-d ₆ ) δ ppm:
1.32-1.44 (2H, m), 1.68-1.86
(4H, m), 2.95-3.04 (2H, m), 3.
45-3.58 (4H, m), 4.64 (2H, t, J
= 4.7Hz), 6.87 (1H, s), 7.50-
7.58 (3H, m), 7.81-7.85 (2H,
m), 9.94-10.05 (1H, brs).

Example 71 5-Phenyl-3- (2- (1-pyrrolidinyl) ethoxy) isoxazole hydrochloride (Exemplary Compound No. 135)
0) (a) 5-Phenyl-3- (2- (1-pyrrolidinyl) ethoxy) isoxazole Piperidine (710 mg) was added to 3- (2-bromoethoxy) -5-phenylisoxazole (268 mg), and the mixture was heated at 100 ° C. For 1 hour. Ice water (20m
After l) was added, ether extraction (20 ml × 2) was performed, and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give the desired compound (2).
11 mg, 82%) as colorless crystals. Melting point: 61-62 ° C; IR spectrum (KBr) ν _max cm ^-1 : 162
3,1596,1575,1509; NMR spectrum (CDCl ₃ ) δ ppm: 1.7
7-1.87 (4H, m), 2.57-2.65 (4
H, m), 2.92 (2H, t, J = 5.5 Hz),
4.43 (2H, t, J = 5.5 Hz), 6.18 (1
H, s), 7.40-7.48 (3H, m), 7.69.
-7.75 (2H, m).

(B) 5-phenyl-3- (2- (1-
Pyrrolidinyl) ethoxy) isoxazole hydrochloride 5-phenyl-3- (2- (1-pyrrolidinyl) ethoxy) isoxazole (200 mg) was reacted in the same manner as in Example 1 (b), and post-treated to give the target compound (211 mg). , 93%) as colorless crystals. Melting point: 182-184 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 298
2,2950,2884,2848,2671,265
3,2607,2560,2480,1619,159
5,1576,1511; NMR spectrum (DMSO-d ₆ ) δ ppm:
1.83-2.08 (4H, m), 3.01-3.21
(2H, m), 3.50-3.68 (4H, m), 4.
60 (2H, t, J = 5.1 Hz), 6.87 (1H,
s), 7.50-7.58 (3H, m), 7.81-
7.87 (2H, m), 10.63 (1H, brs).

Example 72 3- (2- (4-morpholinyl) ethoxy) -5-phenylisoxazole hydrochloride (Exemplary Compound No. 29) (a) 3- (2- (4-morpholinyl) ethoxy)-
5-Phenylisoxazole Morpholine (871 mg) was added to 3- (2-bromoethoxy) -5-phenylisoxazole (268 mg), and the mixture was stirred at 100 ° C for 1 hour. Ice water (20m
After l) was added, ether extraction (20 ml × 2) was performed, and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give the desired compound (2).
(50 mg, 91%) as colorless crystals. Melting point: 66-67 ° C; IR spectrum (KBr) ν _max cm ^-1 : 315
2,1623,1596,1575,1512; NMR spectrum (CDCl ₃ ) δ ppm: 2.5
7 (2H, t, J = 5.4 Hz), 2.82 (2H,
t, J = 5.4 Hz), 3.75 (2H, t, J = 5.
5 Hz), 4.44 (2H, t, J = 5.5 Hz),
6.17 (1H, s), 7.41-7.50 (3H,
m), 7.69-7.76 (2H, m).

(B) 3- (2- (4-morpholinyl)
(Ethoxy) -5-phenylisoxazole hydrochloride 3- (2- (4-morpholinyl) ethoxy) -5-phenylisoxazole (200 mg) was reacted in the same manner as in Example 1 (b) and worked up. As a result, the target compound (202 mg, 89%) was obtained as colorless crystals. Melting point: 180-182 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 298
1,925,2897,2878,2683,264
6,2584,2512,2469,2429,162
0, 1595, 1576, 1512; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.10-3.25 (2H, m), 3.40-3.55
(2H, m), 3.55-3.65 (2H, m), 3.
70-3.85 (2H, m), 3.90-4.05 (2
H, m), 4.67 (2H, brs), 6.86 (1
H, s), 7.50-7.58 (3H, m), 7.81.
−7.87 (2H, m), 10.96 (1H, br)
s).

Example 73 5-Phenyl-3- (2- (1-piperazinyl) ethoxy) isoxazole dihydrochloride (Exemplary Compound No .: 13
51) (a) 3- (2- (4-N-tert-butoxycarbonyl-1-piperazinyl) ethoxy) -5-phenylisoxazole 3- (2-bromoethoxy) -5-phenylisoxazole (268 mg) ) Was dissolved in methanol (1.0 ml), piperazine (861 mg) was added, and the mixture was heated under reflux for 3 hours. The reaction solution was added to a diluted saline solution (40 ml),
After performing dichloromethane extraction (40 ml × 2), the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in dichloromethane (5 ml), ditertiary butyl dicarbonate (1.09 g) was added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/1) to give the desired compound (310 mg, 83%). Was obtained as colorless crystals. Melting point: 110-111 ° C; IR spectrum (KBr) ν _max cm ^-1 : 314
6,1696,1626,1598,1577,151
4; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 2.51 (2H, t, J = 5.0H)
z), 2.83 (2H, t, J = 5.5 Hz), 3.4
7 (2H, t, J = 5.0 Hz), 4.43 (2H,
t, J = 5.5 Hz), 6.16 (1H, s), 7.4
1-7.49 (3H, m), 7.69-7.75 (2
H, m).

(B) 5-phenyl-3- (2- (1-
Piperazinyl) ethoxy) isoxazole dihydrochloride 3- (2- (4-tert-butoxycarbonyl-1)
-Piperazinyl) ethoxy) -5-phenylisoxazole (250 mg) was reacted in the same manner as in Example 1 (b) and post-treated to give the target compound (222 mg,
95%) as colorless crystals. Melting point: 216-222 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 344
3,3189,3123,3001,2972,295
0, 2915, 2771, 2715, 2623, 252
7,2422,1704,1648,1621,159
6,1578,1565,1514; NMR Spectrum (DMSO-d ₆₎ δppm:
3.00-3.85 (10H, brs), 4.64 (2
H, brs), 6.86 (1H, s), 7.50-7.
57 (3H, m), 7.82-7.85 (2H, m),
9.10-9.80 (1H, brs).

Example 74 3- (2-N-methylaminoethoxy) -5-phenylisoxazole hydrochloride (Exemplary Compound No .: 25) (a) 3- (2- (N-tert-butoxycarbonyl-N) -Methylamino) ethoxy) -5-phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (304
mg) in dimethylformamide (3 ml),
Sodium hydride [> 55% (oiliness), 52 mg] was added, and the mixture was stirred at room temperature for 1 hour. After cooling the reaction solution to 5 ° C., methyl iodide (220 mg) was added, and the mixture was stirred at the same temperature for 15 minutes and further at room temperature for 1 hour. After completion of the reaction, the reaction solution was added to ice water (20 ml) and extracted with ether (20 ml ×
After performing 2), the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4/1) to give the desired compound (296 mg, 93%) as a colorless substance. As crystals. Melting point: 72-73 ° C; IR spectrum (KBr) ν _max cm ^-1 : 312
5,1680,1626,1596,1578,151
4; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
9 (9H, s), 2.97 (3H, s), 3.64 (2
H, brs), 4.41 (2H, brs), 6.14.
(1H, s), 7.41-7.52 (3H, m), 7.
69-7.75 (2H, m).

(B) 3- (2-methylaminoethoxy) -5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonyl-N
-Methylamino) ethoxy) -5-phenylisoxazole (250 mg) was reacted in the same manner as in Example 1 (b) and worked up to give the target compound (197 mg,
99%) as colorless crystals. Melting point: 219-221 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 313
4,3022,2981,954,2883,286
9,2843,2803,2785,2734,162
1,1597,1578,1516; NMR spectrum (DMSO-d ₆ ) δ ppm:
2.62 (3H, s), 3.37 (2H, t, J = 5.
1Hz), 4.50 (1H, t, J = 5.1Hz),
6.85 (1H, s), 7.50-7.58 (3H,
m), 7.82-7.88 (2H, m), 8.79 (2
H, brs).

Example 75 3- (2-Acetylaminoethoxy) -5-phenylisoxazole (Exemplary Compound No .: 1347) 3- (2-Aminoethoxy) -5-phenylisoxazole hydrochloride (240 mg) was obtained. After suspending in anhydrous tetrahydrofuran (5 ml) and cooling to 5 ° C., acetyl chloride (94 mg) and triethylamine (243 mg) were added, and the mixture was stirred at the same temperature for 30 minutes. After completion of the reaction, the reaction solution was added to ice water (40 ml), and extracted with ethyl acetate (40 ml).
After performing lx2), the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure,
The obtained crystals were recrystallized from ethyl acetate to give the target compound (225 mg, 91%) as colorless crystals. Melting point: 144-145 ° C; IR spectrum (KBr) ν _max cm ^-1 : 331
6,1641,1624,1597,1578,154
7,1509; NMR spectrum (CDCl ₃ ) δ ppm: 2.0
3 (3H, s), 3.70 (2H, q, J = 5.1H
z), 4.39 (2H, q, J = 5.1 Hz), 6.1
6 (1H, brs), 6.26 (1H, s), 7.41
−7.49 (3H, m), 7.70-7.75 (2H,
m).

Example 76 3- (2-Benzoylaminoethoxy) -5-phenylisoxazole (exemplary compound number: 1349) 3- (2-Aminoethoxy) -5-phenylisoxazole hydrochloride (240 mg) was obtained. After suspending in anhydrous tetrahydrofuran (5 ml) and cooling to 5 ° C, benzoyl chloride (168 mg) and triethylamine (243 m
g) was added and the mixture was stirred at the same temperature for 30 minutes. After the reaction,
The reaction solution was added to ice water (40 ml), extracted with ethyl acetate (40 ml × 2), and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from ethyl acetate to give the target compound (276 mg, 90%) as colorless crystals. Melting point: 129-130 ° C; IR spectrum (KBr) ν _max cm ^-1 : 335
9,1641,1626,1597,1578,153
4,1518; NMR spectrum (CDCl ₃ ) δ ppm: 3.9
2 (2H, q, J = 5.1 Hz), 4.52 (2H,
q, J = 5.1 Hz), 6.17 (1H, s), 6.7
4 (1H, brs), 7.42-7.53 (6H,
m), 7.71-7.74 (2H, m), 7.79-
7.88 (2H, m).

Example 77 3- (2-methoxycarbonylaminoethoxy) -5
Phenylisoxazole (Exemplary Compound No .: 134
8) 3- (2-Aminoethoxy) -5-phenylisoxazole hydrochloride (240 mg) was suspended in anhydrous tetrahydrofuran (5 ml), cooled to 5 ° C, and then methyl chloroformate (113 mg) and triethylamine (243 m).
g) was added and the mixture was stirred at the same temperature for 30 minutes. After the reaction,
The reaction solution was added to ice water (40 ml), extracted with ethyl acetate (40 ml × 2), and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized using a mixed solvent of ethyl acetate and ether to give the target compound (233 mg, 89%) as colorless crystals. Melting point: 95-96 ° C; IR spectrum (KBr) ν _max cm ^-1 : 329
3,1729,1624,1596,1577,155
2,1516; NMR spectrum (CDCl ₃ ) δ ppm: 3.6
3 (2H, q, J = 5.1 Hz), 3.70 (3H,
s), 4.37 (2H, q, J = 5.1 Hz), 5.1.
1 (1H, brs), 6.14 (1H, s), 7.40
−7.49 (3H, m), 7.69-7.75 (2H,
m).

Example 78 3- (2-Aminoethylthio) -5-phenylisoxazole hydrochloride (Exemplary Compound No .: 15) (a) 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-Phenylisoxazole 2- (N-tert-butoxycarbonylamino) ethanethiol (300 mg) was dissolved in dimethylformamide (3.0 ml), cooled to 5 ° C, and then sodium under hydrogen [> 55% ( , 73 mg], and the mixture was stirred and stirred at the same temperature for 30 minutes. Then 3-chloro-5-
Phenylisoxazole (300 mg) was added, and the mixture was stirred at the same temperature for 30 minutes and further at room temperature for 3 days. After the reaction,
The reaction solution was added to ice water (40 ml), extracted with ethyl acetate (40 ml × 2), and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to give the desired compound (130 mg,
24%) as colorless crystals.

Melting point: 87-88 ° C; IR spectrum (KBr) ν _max cm ^-1 : 337
6,1682,1613,1572,1521,149
4; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
4 (9H, s), 3.27 (2H, t, J = 6.3H
z), 3.53 (2H, q, J = 6.3 Hz), 5.0
1 (1H, brs), 6.44 (1H, s), 7.42
−7.50 (3H, m), 7.71-7.76 (2H,
m).

(B) 3- (2-aminoethylthio)-
5-Phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-phenylisoxazole (64
mg) was reacted in the same manner as in Example 1 (b) and worked up to give the target compound (40 mg, 78%) as colorless crystals. Melting point: 196-198 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 314
1,988,2951,923,1609,159
0,1569,1492; NMR Spectrum (DMSO-d ₆₎ δppm:
3.18 (2H, t, J = 7.2 Hz), 3.36 (2
H, t, J = 7.2 Hz), 7.23 (1H, s),
7.53-7.59 (3H, m), 7.83-7.97
(2H, m), 7.97 (3H, brs).

Example 79 3- (2-Aminoethoxy) -4-isopropyl-5
(3-Pyridyl) isoxazole dihydrochloride (Exemplary Compound No .: 1065) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isopropyl-5- (3
-Pyridyl) isoxazole 3-hydroxy-4-isopropyl-5- (3-pyridyl) isoxazole (0.12 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.0
9g) was reacted in the same manner as in Example 9 (a) and worked up to give the target compound (0.14 g, 74%) as a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 332
3,3247,2979,1753,1690; NMR spectrum (CDCl ₃ ) δ ppm: 1.3
1 (6H, d, J = 6.8 Hz), 1.46 (9H,
s), 3.06 (1H, qq, J = 6.8 Hz, J =
6.8 Hz), 3.60 (2H, q, J = 5.2H)
z), 4.39 (2H, t, J = 5.2 Hz), 4.8
4 (1H, brs), 7.43 (1H, dd, J = 8.
0 Hz, J = 4.7 Hz), 7.90 (1H, ddd,
J = 8.0 Hz, J = 2.0 Hz, J = 1.4 Hz),
8.69 (1H, dd, J = 4.7 Hz, J = 1.4H
z), 8.83 (1H, d, J = 2.0 Hz).

(B) 3- (2-aminoethoxy) -4
Implement -isopropyl-5- (3-pyridyl) isoxazole dihydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isopropyl-5- (3-pyridyl) isoxazole (0.13 g) The target compound (0.07 g, 64%) was obtained as colorless crystals by carrying out the reaction and post-treatment in the same manner as in Example 9 (b). Melting point: 193-197 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 304
9, 2963, 2874, 1549; NMR spectrum (DMSO-d ₆ ) δ ppm:
1.27 (6H, d, J = 7.0 Hz), 3.03 (1
H, qq, J = 7.0 Hz, J = 7.0 Hz), 3.2
9 (2H, t, J = 5.4 Hz), 4.48 (2H,
t, J = 5.4 Hz), 7.68 (1H, dd, J =
8.0 Hz, J = 5.0 Hz), 8.12 (1H, dd)
d, J = 8.0 Hz, J = 2.0 Hz, J = 1.4 H
z), 8.28 (3H, brs), 8.78 (1H, d
d, J = 5.0 Hz, J = 1.4 Hz), 8.85 (1
H, d, J = 2.0 Hz).

Example 80 3- (2-Aminoethoxy) -4- (1-chloropropyl) -5-phenylisoxazole hydrochloride (Exemplary Compound No .: 1802) (a) 3- (2- (N- Tert-butoxycarbonylamino) ethoxy) -4- (1-hydroxypropyl) -5-phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0. 2
g), butyllithium (1.6 M hexane solution, 0.9
ml) and propionaldehyde (0.06 ml) were reacted in the same manner as in Example 44 (a) and worked up to give the desired compound (0.14 g, 58%) as a colorless oil. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 36
02, 3459, 2980, 2937, 1712; NMR spectrum (CDCl ₃ ) δ ppm: 0.9
5 (3H, t, J = 7.4 Hz), 1.45 (9H,
s), 1.83-2.08 (2H, m), 2.51 (1
H, brs), 3.57 (2H, q, J = 5.2H)
z), 4.39 (2H, t, J = 5.2 Hz), 4.6
8 (1H, t, J = 7.2 Hz), 4.94 (1H, b
rs), 7.43-7.52 (3H, m), 7.64-
7.75 (2H, m).

(B) 3- (2-aminoethoxy) -4
-(1-chloropropyl) -5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (1-hydroxypropyl) -5
-Phenyl isoxazole (0.13 g) in Example 1
The target compound (0.10 g, 91%) was obtained as colorless crystals by carrying out the same reaction as in (b) and post-treatment. Melting point: 122-124 ° C; IR spectrum (KBr) ν _max cm ^-1 : 297
4,2936,2878,1631,1600,157
7; NMR spectrum (DMSO-d ₆ ) δ ppm:
0.94 (3H, t, J = 7.3 Hz), 2.11
2.28 (2H, m), 3.31 (2H, t, J = 5.
1 Hz), 4.50 (2H, t, J = 5.1 Hz),
5.14 (1H, t, J = 6.5Hz), 7.61-
7.65 (3H, m), 7.72-7.75 (2H,
m).

Example 81 3- (2-Aminoethoxy) -4- (1-chloroisobutyl) -5-phenylisoxazole hydrochloride (Exemplary Compound No .: 1804) (a) 3- (2- (N- Tert-butoxycarbonylamino) ethoxy) -4- (1-hydroxyisobutyl) -5-phenylisoxazole 3- (2- (N-
Tertiary butoxycarbonylamino) ethoxy)-
5-phenylisoxazole (0.2 g), butyllithium (1.6 M in hexane, 0.9 ml) and isobutyraldehyde (0.07 ml) were reacted in the same manner as in Example 44 (a) and worked up. As a result, the target compound (0.21 g, 84%) was obtained as a colorless oily substance. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 36
06,3459,2981,937,1712,16
37; NMR spectrum (CDCl ₃ ) δ ppm: 0.7
9 (3H, d, J = 6.6 Hz), 1.11 (3H, d, J = 6.6 Hz)
d, J = 6.6 Hz), 1.45 (9H, s), 2.1
6-2.29 (1H, m), 2.56 (1H, br)
s), 3.58 (2H, q, J = 5.1 Hz), 4.3
0-4.48 (3H, m), 4.94 (1H, br)
s), 7.46-7.51 (3H, m), 7.70-
7.74 (2H, m).

(B) 3- (2-aminoethoxy) -4
-(1-chloroisobutyl) -5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (1-hydroxyisobutyl)-
Example 5 5-phenylisoxazole (0.20 g)
The target compound (0.11 g, 65%) was obtained as colorless crystals by carrying out the same reaction as in (b) and post-treatment. Melting point: 165-167 ° C; IR spectrum (KBr) ν _max cm ^-1 : 296
7, 2902, 2870, 1636, 1600; NMR spectrum (DMSO-d ₆ ) δ ppm:
0.78 (3H, d, J = 6.6 Hz), 1.15 (3
H, d, J = 6.6 Hz), 2.53-2.63 (1
H, m), 3.30 (2H, t, J = 5.2 Hz),
4.50 (2H, t, J = 5.2 Hz), 4.85 (1
H, d, J = 10.7 Hz), 7.60-7.65 (3
H, m), 7.71-7.75 (2H, m), 8.25
(3H, brs).

Example 82 3- (2-Aminoethoxy) -4- (1-chloroisopentyl) -5-phenylisoxazole hydrochloride (Exemplary Compound No .: 1806) (a) 3- (2- (N -Tert-butoxycarbonylamino) ethoxy) -4- (1-hydroxyisopentyl) -5-phenylisoxazole 3- (2- (N
-Tert-butoxycarbonylamino) ethoxy)
Example 44 (a) was obtained by adding -5-phenylisoxazole (0.2 g), butyllithium (1.6 M hexane solution, 0.9 ml) and isovaleraldehyde (0.09 ml).
The target compound (0.2 g, 77%) was obtained as a colorless oily substance by post-treatment. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 36
01,3459,2981,961,293,17
12,1639; NMR spectrum (CDCl ₃ ) δ ppm: 0.8
7 (3H, d, J = 6.3 Hz), 0.92 (3H,
d, J = 6.3 Hz), 1.45 (9H, s), 1.6
3-1.78 (2H, m), 1.83-1.98 (1
H, m), 3.58 (2H, q, J = 5.2 Hz),
4.40 (2H, t, J = 5.2 Hz), 4.75 −
5.00 (2H, m), 7.44-7.50 (3H,
m), 7.66-7.71 (2H, m).

(B) 3- (2-aminoethoxy) -4
-(1-Chloroisopentyl) -5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (1-hydroxyisopentyl)
By reacting -5-phenylisoxazole (0.19 g) in the same manner as in Example 1 (b) and performing post-treatment, the target compound (0.11 g, 69%) was obtained as colorless crystals. Melting point: 134-136 ° C; IR spectrum (KBr) ν _max cm ^-1 : 296
1,905,2873,1630; NMR spectrum (DMSO-d ₆ ) δppm:
0.79 (3H, d, J = 6.6 Hz), 0.82 (3
H, d, J = 6.6 Hz), 1.57 (1H, qq, J
= 6.6 Hz, J = 6.6 Hz), 2.00-2.12
(2H, m), 3.31 (2H, t, J = 5.4H
z), 4.51 (2H, t, J = 5.4 Hz), 5.2
1 (1H, t, J = 8.0 Hz), 7.62-7.65
(3H, m), 7.69-7.72 (2H, m), 8.
22 (3H, brs).

Example 83 3- (2-Aminoethoxy) -5- (2,4-difluorophenyl) -4-isopropylisoxazole hydrochloride (Exemplary Compound No .: 99) (a) 3- (2- ( N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-difluorophenyl) -4-isopropylisoxazole 5- (2,4-difluorophenyl) -3-hydroxy-4-isopropylisoxazole ( 0.2g) and 2-
By reacting (N-tert-butoxycarbonylamino) ethanol (0.16 g) in the same manner as in Example 1 (a) and performing post-treatment, the target compound (0.25 g,
78%) as a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 340
0, 2980, 2936, 1683; NMR spectrum (CDCl ₃ ) δ ppm: 1.2
2 (6H, d, J = 6.9 Hz), 1.46 (9H,
s), 2.78 (1H, qq, J = 6.9 Hz, J =
6.9 Hz), 3.59 (2H, q, J = 5.2H)
z), 4.38 (2H, t, J = 5.2 Hz), 4.8
6 (1H, brs), 6.90-7.03 (2H,
m), 7.42-7.50 (1H, m).

(B) 3- (2-aminoethoxy) -5
-(2,4-difluorophenyl) -4-isopropylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-difluorophenyl)
-4-Isopropylisoxazole (0.24 g) was reacted in the same manner as in Example 1 (b), and post-treated to give the target compound (0.17 g, 85%) as colorless crystals. Melting point: 177-179 ° C; IR spectrum (KBr) ν _max cm ^-1 : 297
3,2936,1642,1614,1590; NMR spectrum (DMSO-d ₆ ) δppm:
1.18 (6H, d, J = 6.9 Hz), 2.76 (1
H, qq, J = 6.9 Hz, J = 6.9 Hz), 3.2
9 (2H, t, J = 5.3 Hz), 4.46 (2H,
t, J = 5.3 Hz), 7.28-7.33 (1H,
m), 7.50-7.56 (1H, m), 7.60-
7.66 (1H, m), 8.12 (3H, brs).

Example 84 3- (2-aminoethoxy) -4-isopropyl-5
(4-Methylphenyl) isoxazole hydrochloride (Exemplary Compound No .: 266) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isopropyl-5- (4
-Methylphenyl) isoxazole 3-hydroxy-4-isopropyl-5- (4-methylphenyl) isoxazole (0.2 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.16 g) were prepared in Example 1 ( The target compound (0.27 g, 82
%) As a colorless powder. IR spectrum (KBr) ν _max cm ^-1 : 338
3,2965,1686; NMR spectrum (CDCl ₃ ) δ ppm: 1.2
8 (6H, d, J = 7.0 Hz), 1.46 (9H,
s), 2.41 (3H, s), 3.06 (1H, qq,
J = 7.0 Hz, J = 7.0 Hz), 3.59 (2H,
q, J = 5.2 Hz), 4.37 (2H, t, J = 5.
2 Hz), 4.84 (1H, brs), 7.27 (2
H, d, J = 8.1 Hz), 7.46 (2H, d, J =
8.1 Hz).

(B) 3- (2-aminoethoxy) -4
-Isopropyl-5- (4-methylphenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isopropyl-5- (4-methylphenyl) isoxazole (0.25 g) Example 1
The target compound (0.13 g, 65%) was obtained as colorless crystals by carrying out the same reaction as in (b) and post-treatment. Melting point: 208-210 ° C; IR spectrum (KBr) ν _max cm ^-1 : 297
1,877,1641,1522; NMR spectrum (DMSO-d ₆ ) δppm:
1.25 (6H, d, J = 7.0 Hz), 2.38 (3
H, s), 3.02 (1H, qq, J = 7.0 Hz, J
= 7.0 Hz), 3.28 (2H, t, J = 5.2H)
z), 4.44 (2H, t, J = 5.2 Hz), 7.3
7 (2H, d, J = 8.1 Hz), 7.47 (2H,
d, J = 8.1 Hz), 8.20 (3H, brs).

Reference Example 1 4-chloro-5- (4-chlorophenyl) -3-hydroxyisoxazole (a) 4-chlorocinnamic acid ethyl ester 4-chlorocinnamic acid (300 g) was added to benzene (1200 m).
l), ethanol (340 g) and concentrated sulfuric acid (14 ml) were added, and the mixture was heated under reflux for 15 hours. The reaction solution was washed with diluted saline (500 ml), a saturated aqueous solution of sodium hydrogencarbonate (500 ml), and diluted saline (500 ml) in that order, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent is distilled off under reduced pressure, and the obtained residue is distilled under reduced pressure to obtain the target compound (3).
34 g, 97%) as a colorless liquid. Boiling point: 147 to 148 ° C. (4 mmHg); NMR spectrum (CDCl ₃ ) δ ppm: 1.3
3 (3H, t, J = 7.0 Hz), 4.30 (2H,
q, J = 7.0 Hz), 6.47 (1H, d, J = 1)
6.0Hz), 7.63 (1H, d, J = 16.0H)
z), 7.63 (4H, ca.s).

(B) α, β-Dibromo-4-chlorocinnamic acid ethyl ester 4-chlorocinnamic acid ethyl ester (330 g) was dissolved in carbon tetrachloride (1200 ml), and bromine (251 g) was added dropwise with stirring at room temperature. did. After stirring at room temperature for 4 hours, the mixture was left overnight. The solvent was distilled off under reduced pressure to obtain the target compound (572 g, 99%) as colorless crystals. Melting point: 67-68 ° C; NMR spectrum (CDCl ₃ ) δ ppm: 1.3
4 (3H, t, J = 7.0 Hz), 4.37 (2H,
q, J = 7.0 Hz), 4.80 (1H, d, J = 1)
2.0Hz), 5.32 (1H, d, J = 12.0H)
z), 7.37 (4H, ca.s).

(C) 5- (4-chlorophenyl) -3
-Hydroxyisoxazole Sodium hydroxide (151 g) was added to methanol (600 m
l), an aqueous solution (50 ml) of hydroxylamine hydrochloride (45 g) was added dropwise with stirring at 0 ° C, and then a solution of ethyl α, β-dibromo-4-chlorocinnamate (200 g) in dioxane (200 ml) was added. Was added dropwise. The mixture was stirred at room temperature for 4 hours, heated under reflux for 5 hours, cooled to 5 ° C., adjusted to pH 2 with concentrated hydrochloric acid, and added to water (5 L). The precipitated crystals were collected by filtration, washed with water (2 L), and then washed with ethanol (1 L).
L) to give 90 g (85%) of the target compound as a pale yellow powder. Mp: 215-220 ° C. (decomposition); NMR Spectrum _{(DMF-d 7) δppm:} 6.
66 (1H, s), 7.52-8.20 (4H, m),
11.5-12.0 (1H, brs).

(D) 4-Chloro-5- (4-chlorophenyl) -3-hydroxyisoxazole 5- (4-Chlorophenyl) -3-hydroxyisoxazole (50.0 g) was added to dry tetrahydrofuran (30
0 ml), and sulfuryl chloride (34.5 g) dissolved in dry benzene (50 ml) was added dropwise with stirring at 5 ° C. After stirring at the same temperature for 30 minutes, stirring at room temperature for 1 hour, and further heating and refluxing for 3 hours, the solvent was distilled off under reduced pressure, and the obtained solid was recrystallized from ethanol to obtain the target compound ( 44.2 g, 76.8
%) As colorless needles. Mp: 235-238 ° C. (decomposition); NMR Spectrum _{(DMF-d 7) δppm:} 7.
60-8.20 (4H, m), 12.6-13.6 (1
H, brs).

Reference Example 2 3-hydroxy-5- (2-thienyl) isoxazole 2-thiophenacrylic acid was prepared in Reference Example 1 (a), Reference Example 1
(B) Then, the reaction was carried out in the same manner as in Reference Example 1 (c), and post-treatment was carried out to obtain a target compound. Melting point: 163-165 ° C .; NMR spectrum (DMSO-d ₆ ) δ ppm:
6.38 (1H, s), 7.20-7.25 (1H,
m), 7.60-7.80 (2H, m), 11.2-1
1.6 (1H, brs).

Reference Example 3 4-Chloro-3-hydroxy-5- (2-thienyl) isoxazole 3-hydroxy-5- (2-thienyl) isoxazole was reacted in the same manner as in Reference Example 1 (d), and post-treated. Thereby, the target compound was obtained. Melting point: 191-194 ° C .; NMR spectrum (DMF-d ₇ ) δ ppm: 7.
21-7.45 (1H, m), 7.70-8.20 (2
H, m), 10.0-13.0 (1H, brs).

Reference Example 4 3-Hydroxy-5- (3-pyridyl) isoxazole 3-pyridineacrylic acid was prepared in Reference Example 1 (a), Reference Example 1
(B) Then, the reaction was carried out in the same manner as in Reference Example 1 (c), and post-treatment was carried out to obtain a target compound. Melting point: 212-214 ° C (decomposition); NMR spectrum (DMF-d ₇ ) δ ppm:
76 (1H, s), 7.40-7.80 (1H, m),
8.10-8.50 (1H, m), 8.66-9.00
(1H, m), 9.05-9.33 (1H, m).

Reference Example 5 4-chloro-3-hydroxy-5- (2-pyridyl) isoxazole 3-hydroxy-5- (2-pyridyl) isoxazole was reacted in the same manner as in Reference Example 1 (d) and post-treated. Thereby, a target compound is obtained. REFERENCE EXAMPLE 6 Ethyl 3-hydroxy-4-isopropyl-5-phenylisoxazole benzoylacetate was converted to agricultural and biological chemistry, vol. 50, p. 1831 (1986) [ Agric. Biol. Chem., EN , 50 , 1831 (198
6).] To give the target compound. Melting point: 203-205 ° C; NMR spectrum (DMSO-d ₆ ) δ ppm:
1.24 (6H, d, J = 7.1 Hz), 3.01 (1
H, q, J = 7.1 Hz), 7.47-7.61 (5
H, m), 11.2-11.6 (1H, brs).

Reference Example 7 2- (N-tert-butoxycarbonylamino) ethanol 2-Aminoethanol (6.1 g) was dissolved in a mixture of tetrahydrofuran and water (1: 1, 100 ml) and stirred under ice-cooling with stirring. Shale butyl dicarbonate (2
1.8 g) was added dropwise, and the mixture was stirred at the same temperature for 1 hour and further at room temperature for 5 hours. Ethyl acetate (200 ml) was added to the reaction solution, washed with water, the organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to give the target compound (15.3 g, 95%). %) As a colorless oil. Rf value: 0.35 (developing solvent: cyclohexane / ethyl acetate = 1/1); NMR spectrum (CDCl ₃ ) δ ppm: 1.4
5 (9H, s), 2.35-2.50 (1H, br
s), 3.29 (2H, q, J = 5.3 Hz), 3.7
1 (2H, q, J = 5.3 Hz), 4.85-5.05
(1H, brs). Reference Example 8 4- (tert-butyl) -3-hydroxy-5-phenylisoxazole (a) 2-benzoyl-3,3-dimethylbutyric acid ethyl ester diisopropylamine (5.6 ml) was dissolved in tetrahydrofuran (56 ml). Butyllithium (1.6 M hexane solution, 25 m
l) was added dropwise and stirred for 15 minutes. After the reaction solution was cooled to -70 ° C, 3,3-dimethylbutyric acid ethyl ester (6.7 ml) was added dropwise, and the mixture was stirred for 10 minutes. Stirred. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 20/1) to give the desired compound (4.5 g, 91 g). %) As a colorless oil. (B) 4- (tert-butyl) -3-hydroxy-5-phenylisoxazole 2-benzoyl-3,3-dimethylbutyric acid ethyl ester (2.0 g) was dissolved in methanol (20 ml),
Sodium methoxide (28
% Methanol solution, 1.6 ml) was added dropwise, followed by stirring for 10 minutes. After cooling the reaction solution to −30 ° C., a methanol suspension (10 ml) of hydroxylamine hydrochloride (1.1 g) and sodium methoxide (28% methanol solution, 6.2 ml) was added dropwise, and the mixture was heated at the same temperature for 30 minutes. After stirring, 6N hydrochloric acid (14 ml) was added, and the mixture was stirred at 80 ° C for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was poured into ice water, extracted with ethyl acetate, and the organic layer was washed with brine and dried using anhydrous magnesium sulfate. . After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was crystallized using isopropyl ether to give the desired compound (0.35 g, 20%) as colorless crystals. IR spectrum (KBr) ν _max cm ^-1 : 302
7, 2993, 2960, 2936, 2869, 279
0, 2697, 2623, 2574, 1644, 160
0; NMR spectrum (CDCl ₃ ) δ ppm: 1.2
2 (9H, s), 7.39-7.50 (5H, m).

Reference Example 9 5- (4-chlorophenyl) -3-hydroxy-4-isopropylisoxazole (a) 2- (4-chlorobenzoyl) isovaleric acid ethyl ester 4-chlorobenzoyl chloride (2.5 ml) Was reacted with ethyl isovaleric acid ethyl ester (1.5 ml) in the same manner as in Reference Example 8 (a), followed by post-treatment to obtain the target compound (2.2 g, 82%) as a colorless oily substance. (B) 5- (4-chlorophenyl) -3-hydroxy-4-isopropylisoxazole 2- (4-chlorobenzoyl) isovaleric acid ethyl ester (2.1 g), hydroxylamine hydrochloride (1.1
g) and sodium methoxide (28% methanol solution, 7.5 ml) were reacted in the same manner as in Reference Example 8 (b).
By post-treatment, the target compound (1.3 g, 71
%) As colorless crystals. IR spectrum (KBr) ν _max cm ^-1 : 306
5,3018,2970,2935,2875,282
0, 2768, 2695, 2609, 1646; NMR spectrum (CDCl ₃ ) δ ppm: 1.3
5 (6H, d, J = 7.0 Hz), 3.06 (1H, q
q, J = 7.0 Hz, J = 7.0 Hz), 7.46 (2
H, d, J = 8.6 Hz), 7.54 (2H, d, J =
8.6 Hz). Reference Example 10 5- (2,4-difluorophenyl) -3-hydroxyisoxazole (a) 2,4-difluorocinnamic acid ethyl ester 2,4-difluorocinnamic acid (10.1 g) was added to ethanol (100 ml). Dissolve, add concentrated sulfuric acid (1 ml),
The mixture was refluxed for 3 hours. The solvent was distilled off under reduced pressure, and the obtained residue was poured into ice water, extracted with ethyl acetate, and the extract was washed successively with a 5% aqueous sodium hydrogen carbonate solution and a saturated saline solution. Dried with magnesium. After filtration, the solvent was distilled off under reduced pressure to obtain the target compound (11.2 g, 97%) as a colorless oily substance. (B) α, β-Dibromo-2,4-difluorocinnamic acid ethyl ester 2,4-difluorocinnamic acid ethyl ester (11.2
g) was dissolved in carbon tetrachloride (110 ml), and bromine (2.7 ml) was added dropwise with stirring at room temperature, followed by stirring at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain the target compound (19.6 g, quantitative) as a colorless powder. (C) 5- (2,4-difluorophenyl) -3-hydroxyisoxazole Sodium hydroxide (10.9 g) was added to methanol (110
ml), and a solution of hydroxylamine hydrochloride (4.2 g) in water (10 ml) was added dropwise with stirring at 5 ° C.
α, β-Dibromo-2,4-difluorocinnamic acid ethyl ester (19.6 g) in tetrahydrofuran (20 m
l) The solution was added dropwise, and the mixture was stirred at room temperature for 2 hours and then heated under reflux for 5 hours. The solvent was distilled off under reduced pressure, the obtained residue was poured into ice water, the pH of the solution was adjusted to 2 using concentrated hydrochloric acid, extracted with ethyl acetate, and the extract was washed with saturated saline. The organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 1/1) to give the desired compound (8.2 g, 79 g). %) As colorless crystals. IR spectrum (KBr) ν _max cm ^-1 : 317
0, 3090, 3028, 2848, 2806, 268
9,2655,2603,1630; NMR spectrum (DMSO-d ₆ ) δppm:
6.38 (1H, s), 7.25-7.32 (1H,
m), 7.47-7.56 (1H, m), 7.89-
7.99 (1H, m), 11.62 (1H, brs).

Reference Example 11 3-hydroxy-5- (2-trifluoromethylphenyl) isoxazole (a) 2-trifluoromethylcinnamic acid ethyl ester 2-trifluoromethylcinnamic acid (10.1 g), concentrated sulfuric acid (1 ml) Reference Example 10) and ethanol (100 ml)
The target compound (10.8 g, 95%) was obtained as a colorless oil by reacting in the same manner as in (a) and performing post-treatment. (B) α, β-dibromo-2-trifluoromethylcinnamic acid ethyl ester 2-trifluoromethylcinnamic acid ethyl ester (1
0.8 g) and bromine (2.3 ml) were reacted in the same manner as in Reference Example 10 (b), followed by post-treatment to obtain the target compound (17.9 g, quantitative) as a colorless powder. (C) 3-hydroxy-5- (2-trifluoromethylphenyl) isoxazole α, β-dibromo-2-trifluoromethylcinnamic acid ethyl ester (17.9 g), hydroxylamine hydrochloride (3.8 g) and hydroxylated Sodium (9.1 g) was reacted in the same manner as in Reference Example 10 (c) and worked up to give the target compound (7.6 g, 76%) as colorless crystals. IR spectrum (KBr) ν _max cm ^-1 : 317
6,3096,3022,2950,2836,279
6,2669,1620,1600; NMR spectrum (DMSO-d ₆ ) δ ppm:
6.34 (1H, s), 7.73-7.87 (3H,
m), 7.92-7.95 (1H, m), 11.58
(1H, brs).

Reference Example 12 3-hydroxy-5- (4-trifluoromethylphenyl) isoxazole (a) 4-trifluoromethylcinnamic acid ethyl ester 4-trifluoromethylcinnamic acid (10.2 g), concentrated sulfuric acid (1 ml) Reference Example 10) and ethanol (100 ml)
The target compound (10.9 g, 95%) was obtained as a colorless oil by reacting in the same manner as in (a) and performing post-treatment. (B) α, β-dibromo-4-trifluoromethylcinnamic acid ethyl ester 4-trifluoromethylcinnamic acid ethyl ester (1
0.8 g) and bromine (2.4 ml) were reacted in the same manner as in Reference Example 10 (b), followed by post-treatment to obtain the target compound (17.9 g, quantitative) as a colorless powder. (C) 3-hydroxy-5- (4-trifluoromethylphenyl) isoxazole α, β-dibromo-4-trifluoromethylcinnamic acid ethyl ester (17.9 g), hydroxylamine hydrochloride (3.8 g) and hydroxylated The target compound (8.3 g, 83%) was obtained as colorless crystals by reacting sodium (9.1 g) in the same manner as in Reference Example 10 (c) and performing post-treatment. IR spectrum (KBr) ν _max cm ^-1 : 315
4,3018,2987,2838,2788,267
3,2637,2607,2547,1631,161
4; NMR spectrum (DMSO-d ₆ ) δ ppm:
6.77 (1H, s), 7.88 (2H, d, J = 8.
4 Hz), 8.03 (2H, d, J = 8.4 Hz), 1
1.60 (1H, brs).

Reference Example 13 3-Hydroxy-5- (4-isopropylphenyl) isoxazole (a) 4-isopropylcinnamic acid ethyl ester 4-isopropylcinnamic acid (5.0 g), concentrated sulfuric acid (0.5 g)
ml) and ethanol (50 ml) in Reference Example 10 (a).
By subjecting to post-treatment, the target compound (5.5 g, 97%) was obtained as a colorless oily substance. (B) α, β-dibromo-4-isopropylcinnamic acid
Ethyl ester 4-isopropylcinnamic acid ethyl ester (5.5 g)
And bromine (1.3 ml) were reacted in the same manner as in Reference Example 10 (b), and post-treated to give the target compound (9.5 g,
Quantitative) was obtained as a colorless powder. (C) 3-hydroxy-5- (4-isopropylphenyl) isoxazole α, β-dibromo-4-isopropylcinnamic acid ethyl ester (9.5 g), hydroxylamine hydrochloride (2.2)
g) and sodium hydroxide (5.2 g).
The target compound (3.6 g, 71%) was obtained as colorless crystals by carrying out the same reaction as in (c) and post-treatment. IR spectrum (KBr) ν _max cm ^-1 : 301
3,2964,2934,2893,2872,279
3,2665,2631,2542,1624; NMR spectrum (DMSO-d ₆ ) δppm:
1.22 (6H, d, J = 6.9 Hz), 2.94 (1
H, qq, J = 6.9 Hz, J = 6.9 Hz), 6.4
8 (1H, s), 7.39 (2H, d, J = 8.3H
z), 7.72 (2H, d, J = 8.3 Hz).

Reference Example 14 3-Hydroxy-5- (4-phenoxyphenyl) isoxazole (a) 4-phenoxycinnamic acid 4-phenoxybenzaldehyde (10.0 g) and potassium acetate (9.8 g) were treated with acetic anhydride (9. 5 ml) and heated to reflux at 180 ° C. for 5 hours. After completion of the reaction, the pH of the solution was adjusted to 2 using hydrochloric acid, extracted with ethyl acetate, the extract was washed with saturated saline, and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to give the desired compound (6.5 g, 54%). %) As colorless crystals. (B) 4-phenoxycinnamic acid ethyl ester 4-phenoxycinnamic acid (4.0 g), concentrated sulfuric acid (0.4 m
l) and ethanol (40 ml) were reacted in the same manner as in Reference Example 10 (a) and worked up to give the target compound (4.4 g, 98%) as a colorless oil. (C) α, β-Dibromo-4-phenoxycinnamic acid ethyl ester 4-phenoxycinnamic acid ethyl ester (4.4 g) and bromine (0.84 ml) were reacted in the same manner as in Reference Example 10 (b), and post-treated. By doing, the target compound (7.0 g,
Quantitative) was obtained as a colorless powder. (D) 3-hydroxy-5- (4-phenoxyphenyl) isoxazole α, β-dibromo-4-phenoxycinnamic acid ethyl ester (7.0 g), hydroxylamine hydrochloride (1.4)
g) and sodium hydroxide (3.3 g) in Reference Example 10
The target compound (3.4 g, 83%) was obtained as colorless crystals by carrying out the same reaction as in (c) and post-treatment. IR spectrum (KBr) ν _max cm ^-1 : 314
7,3013,2951,852,2785,261
4,2557,1627; NMR spectrum (DMSO-d ₆ ) δ ppm:
6.47 (1H, s), 7.07-7.25 (5H,
m), 7.42-7.48 (2H, m), 7.79-
7.83 (2H, m), 11.36 (1H, brs).

Reference Example 15 3-hydroxy-5- (1-naphthyl) isoxazole (a) 1-naphthylacrylic acid 1-naphthaldehyde (30.5 g), potassium acetate (38.3 g) and acetic anhydride (36.9 ml) ) Was reacted in the same manner as in Reference Example 14 (a) and post-treated to give
The target compound (22.4 g, 58%) was obtained as a colorless powder. (B) 1-naphthylacrylic acid ethyl ester 1-naphthylacrylic acid (9.5 g), concentrated sulfuric acid (1 m
l) and ethanol (100 ml) in Reference Example 10 (a)
The reaction was carried out in the same manner as described above, and the mixture was worked up to give the target compound (10.2 g, 94%) as a colorless oil. (C) α, β-dibromo-1-naphthylacrylic acid
Ethyl ester 1-naphthylacrylic acid ethyl ester (10.1
g) and bromine (2.5 ml) were reacted in the same manner as in Reference Example 10 (b) and post-treated to give the target compound (17.
2 g, quantitative) as a colorless powder. (D) 3-hydroxy-5- (1-naphthyl) isoxazole α, β-dibromo-1-naphthylacrylic acid ethyl ester (6.0 g), hydroxylamine hydrochloride (1.3)
g) and sodium hydroxide (7.2 g).
The target compound (2.6 g, 78%) was obtained as colorless crystals by carrying out the same reaction as in (c) and post-treatment. IR spectrum (KBr) ν _max cm ^-1 : 313
6,3045,3017,2790,2710,264
0,2569,1628; NMR spectrum (DMSO-d ₆ ) δ ppm:
6.53 (1H, s), 7.61-7.70 (3H,
m), 7.84-7.87 (1H, m), 8.03-
8.13 (2H, m), 8.22-8.28 (1H,
m).

Reference Example 16 3-Hydroxy-5- (4-hydroxyphenyl) isoxazole 3-Hydroxy-5- (4-methoxyphenyl) isoxazole (5.0 g) was suspended in dichloromethane (50 ml). 7.0 g) was added and the mixture was refluxed for 66 hours. After the completion of the reaction, the reaction solution was poured into ice water, and 6
After adding normal hydrochloric acid, the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 2/1).
The target compound (3.8 g,
83%) as colorless crystals. IR spectrum (KBr) ν _max cm ^-1 : 314
0,3074,1624,1588; NMR Spectrum (DMSO-d ₆₎ δppm:
6.24 (1H, s), 6.86 (2H, d, J = 8.
2 Hz), 7.62 (2H, d, J = 8.2 Hz), 1
0.03 (1H, s), 11.24 (1H, brs).

Reference Example 17 5- (2,4-difluorophenyl) -3-hydroxy-4-isopropylisoxazole (a) 2- (2,4-difluorobenzoyl) isovaleric acid ethyl ester 2,4-difluoro Reference Example 8: Benzoyl chloride (4.9 ml) and isovaleric acid ethyl ester (3.0 ml)
The target compound (3.65 g, 68%) was obtained as a colorless liquid by carrying out the same reaction as in (a) and post-treatment. (B) 5- (2,4-difluorophenyl) -3-hydroxy-4-isopropylisoxazole 2- (2,4-difluorobenzoyl) isovaleric acid ethyl ester (1.7 g), hydroxylamine hydrochloride (0 9.9 g) and sodium methoxide (28% methanol solution, 7.5 ml) were reacted in the same manner as in Reference Example 8 (b), followed by post-treatment to give the target compound (0.59 g).
g, 39%) as colorless crystals. IR spectrum (KBr) ν _max cm ^-1 : 308
2,3033,2980,2968,2935,291
3,2877,2836,2795,2699,263
6,2604, 1660, 1610; NMR spectrum (DMSO-d ₆ ) δ ppm:
1.28 (6H, d, J = 7.0 Hz), 2.81 (1
H, qq, J = 7.0 Hz, J = 7.0 Hz), 6.9
1-7.05 (2H, m), 7.43-7.52 (1
H, m).

Reference Example 18 4-Cyclopropyl-3-hydroxy-5-phenylisoxazole (a) 2-benzoyl-2-cyclopropylacetic acid methyl ester Benzoyl chloride (1.0 ml) and 2-cyclopropylacetic acid methyl ester (2.0 g) was reacted in the same manner as in Reference Example 8 (a), and post-treated to give the target compound (1.05 g, 28%) as a colorless liquid. (B) 4-cyclopropyl-3-hydroxy-5-phenylisoxazole 2-benzoyl-2-cyclopropylacetic acid methyl ester (0.9 g), hydroxylamine hydrochloride (0.6
g) and sodium methoxide (28% methanol solution, 4.0 ml) were reacted in the same manner as in Reference Example 8 (b).
By post-treatment, the target compound (0.32 g, 39
%) As colorless crystals. IR spectrum (KBr) ν _max cm ^-1 : 308
5,306,3012,2972,2909,285
1,778,2716,2652,2601,164
6; NMR spectrum (CDCl ₃ ) δ ppm: 0.7
9-0.85 (2H, m), 0.91-0.98 (2
H, m), 1.67-1.77 (1H, m), 7.43.
−7.53 (3H, m), 7.86-7.90 (2H,
m).

Reference Example 19 3-hydroxy-4-isopropyl-5- (3-pyridyl) isoxazole (a) ethyl 2-nicotinoylisovalerate nicotinic acid chloride hydrochloride (0.9 g) and ethyl isovaleric acid ester (2 0.3 ml), diisopropylamine (2.1 ml) and butyllithium (1.6 M hexane solution, 9.4 ml) were reacted in the same manner as in Reference Example 8 (a), and post-treated to give the target compound (0.78 g). ,
44%) as a colorless liquid. (B) 3-hydroxy-4-isopropyl-5- (3
-Pyridyl) isoxazole 2-nicotinoylisovaleric acid ethyl ester (0.7
6g), hydroxylamine hydrochloride (0.46 g) and sodium methoxide (28% methanol solution, 3.1 m)
1) was reacted in the same manner as in Reference Example 8 (b) and worked up to give the target compound (0.15 g, 23%) as colorless crystals. IR spectrum (KBr) ν _max cm ^-1 : 306
9,3035,2970,2934,2876,280
9,2770,2709,2665,2605,257
6,2519,1511; NMR spectrum (CDCl ₃ ) δ ppm: 1.3
8 (6H, d, J = 7.0 Hz), 3.10 (1H, q
q, J = 7.0 Hz, J = 7.0 Hz), 7.45 (1
H, dd, J = 7.9 Hz, J = 4.4 Hz), 7.9
4 (1H, d, J = 7.9 Hz), 8.72 (1H,
d, J = 4.4 Hz), 8.88 (1H, s).

Reference Example 20 4-chloro-3-hydroxy-5- (3-pyridyl) isoxazole 3-hydroxy-5- (3-pyridyl) isoxazole was reacted in the same manner as in Reference Example 1 (d) and post-treated. Thereby, the target compound was obtained. Mp: 220-224 ° C. (decomposition); NMR Spectrum _{(DMF-d 7) δppm:} 7.
60-8.20 (4H, m), 12.6-13.6 (1
H, brs).

Test Example 1 A-type monoamine oxidase inhibitory activity Biochemical Pharmacology, Vol. 12, 143
9 (1963) [ Biochem, Pharmacol. , 12 , 1439 (196
3).] And Journal of Neurochemistry,
35, 109 (1980) [ J. Neurochem. , 35 ,
109 (1980).]]. To 30 μl of a mouse brain crude mitochondrial preparation (30 μg protein), 210 μl of a phosphate buffer (pH 7.4) and 30 μl of a test compound (dissolved in 10% DMSO-water) were added, and the mixture was preincubated at 38 ° C. for 20 minutes. . Thereafter, ¹⁴ C-5-hydroxytryptamine (5-HT,
(Final concentration: 100 μM) and reacted at 38 ° C. for 20 minutes. After the reaction was stopped by adding 2N hydrochloric acid (200 μl), the metabolite produced by the enzymatic reaction labeled with ¹⁴ C was extracted with a solvent (ethyl acetate: toluene = 1: 1), and its ¹⁴ C radioactivity was determined. The concentration of the compound that reduces the ¹⁴ C radioactivity of the control by 50% (IC ₅₀ ) was determined by measuring with a liquid scintillation counter. As a result of using this test, for example, Examples 1, 2, 3, 4, 5, 6, 7, 8,
The compounds of 54, 57, 58, 59, ₆₀ , 62 and 67 exhibited particularly excellent effects with IC ₅₀ of 28 nM or less.

Formulation Example 1 Hard Capsule 50 mg of the powdered compound of Example 4, 128.7 mg of lactose, 70 mg of cellulose and 1.3 mg of magnesium stearate were mixed, and the mixture was passed through a 60-mesh sieve. The powder is placed in a 250 mg No. 3 gelatin capsule to make a capsule. Formulation Example 2 Tablets 50 mg of the powdered compound of Example 4, 124 mg of lactose, 25 mg of cellulose and 1 mg of magnesium stearate were mixed, and the mixture was compressed with a tablet machine to give one tablet.
mg tablets. The tablets can be sugar-coated as needed.

[0362]

The isoxazole derivative (I) of the present invention
Has excellent A-type monoamine oxidase inhibitory activity and low toxicity, so depression, Parkinson's disease,
As a therapeutic or preventive drug (especially a therapeutic drug) for neurological diseases (particularly depression) such as Alzheimer-type dementia (cognitive impairment based on Alzheimer's disease) or cerebrovascular dementia (cognitive impairment based on cerebrovascular dementia). Useful.

────────────────────────────────────────────────── ─── front page continued (51) Int.Cl. ⁶ identifications FI C07D 261/12 C07D 261/12 413/04 213 413/04 213 231 231 233 233 261 261 307 307 417/04 261 417/04 261 (72) Inventor Masao Kitsuzuka 1-2-58 Hiromachi, Shinagawa-ku, Tokyo, Japan Sankyo Corporation (72) Inventor Kenji Yoshimi 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Corporation 72) Inventor Kazuo Kaneko 1-58, Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd.

Claims (20)

[Claims] 1. A compound of the general formula {Wherein, R ¹ is the same or different C ₆ which may have 1 to 3 substituents selected from Substituent Group with -C ₁₄
An aryl group or 1 to 3 substituents,
A 5- or 6-membered aromatic heterocyclic group having 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which is the same or different from the group consisting of a halogen atom; ; C ₁ -C ₆ alkyl; halogen or C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl substituted by; C ₁ -C ₆ alkoxy; same or different 1 to 3 of which are selected from the following group Which may have a substituent,
C ₆ -C ₁₄ aryl, C ₇ -C ₁₈ aralkyl, C ₆ -C
₁₄ aryloxy or C ₇ -C ₁₈ aralkyloxy (the group of substituents is halogen, C ₁ -C ₆ alkyl or
It is ₁ -C ₆ alkoxy. ); Cyano; nitro; hydroxyl; C ₁ -C ₇ alkanoyl; C ₁ -C ₇ alkanoyloxy; C ₂ -C ₇ alkoxycarbonyl; amino; carbamoyl; mono (C ₁ -C ₆ alkyl) carbamoyl; di (C ₁ -C ₆ alkyl) carbamoyl and mono-C ₇ -C ₁₅ arylcarbonylamino, which may be identical or different and have 1 to 3 substituents selected from the following group (the group of substituents is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy.). ], R ² is a hydrogen atom; a halogen atom; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkyl group substituted by halogen or C ₁ -C ₆ alkoxy; C ₂ -C ₆ alkenyl group; C
₂ -C ₆ alkynyl group; C ₃ -C ₁₀ cycloalkyl group;
C ₃ -C ₁₀ cycloalkenyl group; C ₁ -C ₆ alkoxy group; a cyano group; a carboxyl group; C ₁ -C ₇ alkanoyl group; C ₂ -C ₇ alkoxycarbonyl group; a carbamoyl group; a mono (C ₁ -C ₆ Alkyl) carbamoyl group or di (C ₁ -C ₆ alkyl) carbamoyl group, R ³ represents an amino group, a mono C ₁ -C ₆ alkylamino group,
Di (C ₁ -C ₆ alkyl) amino group, mono C ₁ -C ₇ alkanoylamino group, mono C ₂ -C ₇ alkoxycarbonylamino group, the same or different, and 1 to 3 substitutions selected from the following groups Mono C ₇ -C _{15 which} may have a group
An arylcarbonylamino group (the group of substituents is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy) or one nitrogen atom, and one nitrogen atom or oxygen atom Represents a 5- or 6-membered saturated heterocyclic group (the group is bonded on a nitrogen atom), X represents an oxygen atom or a sulfur atom, and n is an integer of 2 to 6. Is shown. A type monoamine oxidase inhibitor comprising, as an active ingredient, an isoxazole derivative having｝ or a pharmacologically acceptable salt thereof. 2. A C ₆ -C ₁₄ aryl group or a C ₆ -C ₁₄ aryl group according to claim 1, wherein R ¹ is the same or different and may have 1 to 3 substituents selected from the following substituent groups: A 5- or 6-membered aromatic having 1 or 2 heteroatoms, which may be the same or different and is optionally selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which may have 1 to 3 substituents; An A-type monoamine oxidase inhibitor comprising, as an active ingredient, an isoxazole derivative that is an aromatic heterocyclic group or a pharmaceutically acceptable salt thereof.
[The group of substituents is halogen; C ₁ -C ₆ alkyl;
C ₁ substituted with halogen or C ₁ -C ₆ alkoxy
-C ₆ alkyl; C ₁ -C ₆ alkoxy; same or different groups of 1 to 3 of which may have a substituent C ₆ -C ₁₄ aryl (the substituent is selected from the following group, Halogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy)); benzyl, fluorobenzyl, chlorobenzyl, difluorobenzyl, dichlorobenzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl; phenoxy, 4-fluorophenoxy, 4-chlorophenoxy, 2,4-dichlorophenoxy, 4-methylphenoxy, 4-methoxyphenoxy; benzyloxy, 4-fluorobenzyloxy, 4-chlorobenzyloxy,
2,4-difluorobenzyloxy, 2,4-dichlorobenzyloxy, 4-methylbenzyloxy, 2,4-
Dimethylbenzyloxy, 4-methoxybenzyloxy; cyano; nitro; hydroxyl; acetoxy; C ₂ -C ₇
Alkoxy; amino; carbamoyl; mono (C ₁ -C ₆ alkyl) carbamoyl; di (C ₁ -C ₆₎
Alkyl) carbamoyl; benzoylamino, 4-fluorobenzoylamino, 4-chlorobenzoylamino,
2,4-dichlorobenzoylamino, 4-toluoylamino and 4-anisoylamino. ] 3. A C ₆ -C ₁₄ aryl group or a C ₆ -C ₁₄ aryl group according to claim 1, wherein R ¹ is the same or different and may have 1 to 3 substituents selected from the following substituent groups. A 5- or 6-membered aromatic having 1 or 2 heteroatoms, which may be the same or different and is optionally selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which may have 1 to 3 substituents; An A-type monoamine oxidase inhibitor comprising, as an active ingredient, an isoxazole derivative that is an aromatic heterocyclic group or a pharmaceutically acceptable salt thereof.
[The group of substituents is halogen; C ₁ -C ₆ alkyl;
C ₁ substituted with halogen or C ₁ -C ₆ alkoxy
-C ₆ alkyl; C ₁ -C ₆ alkoxy; same or different groups of 1 to 3 of which may have a substituent C ₆ -C ₁₄ aryl (the substituent is selected from the following group, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy);. cyano; C ₂ -C ₇ alkoxycarbonyl; carbamoyl; mono (C ₁ -C ₆ alkyl) carbamoyl; and di (C ₁ -C ₆ alkyl) carbamoyl. ] 4. A C ₆ -C ₁₄ aryl group or a C ₆ -C ₁₄ aryl group according to claim 1, wherein R ¹ is the same or different and may have 1 to 3 substituents selected from the following substituent groups: A 5- or 6-membered aromatic having 1 or 2 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which may have 1 or 2 said substituents; An A-type monoamine oxidase inhibitor comprising, as an active ingredient, an isoxazole derivative that is an aromatic heterocyclic group or a pharmaceutically acceptable salt thereof.
[The group of the substituents is halogen, C ₁ -C ₄ alkyl,
Fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, methoxymethyl, methoxyethyl, C ₁ -C ₄ alkoxy, phenyl, 4-fluorophenyl, 4-chlorophenyl, 2 , 4-dichlorophenyl, 4-methylphenyl, 4-methoxyphenyl, cyano, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl, N, N-dimethylcarbamoyl and N, N-diethylcarbamoyl. ] 5. The method according to claim 1, wherein R ¹ is the same or different and has 1 to 3 phenyl groups or 1 to 2 phenyl groups which may have 1 to 3 substituents selected from the following substituent groups. An A-type monoamine oxidase inhibitor comprising, as an active ingredient, an isoxazole derivative which is a furyl group, a thienyl group or a pyridyl group, or a pharmaceutically acceptable salt thereof, which may have the substituent. [The group of substituents is halogen, methyl, ethyl, trifluoromethyl, methoxy, phenyl, cyano, methoxycarbonyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl and N, N-dimethylcarbamoyl. ] 6. The phenyl group according to claim 1, wherein R ¹ is the same or different and may have one or two substituents selected from the following substituent groups, or one such substituent. May have,
An A-type monoamine oxidase inhibitor comprising, as an active ingredient, an isoxazole derivative which is a furyl group, a thienyl group or a pyridyl group, or a pharmaceutically acceptable salt thereof. [The group of substituents is fluorine, chlorine, methyl, ethyl, trifluoromethyl and methoxy. ] 7. The method according to claim 1, wherein R ¹ is phenyl, fluorophenyl, chlorophenyl, difluorophenyl, dichlorophenyl, methylphenyl, 2-phenyl,
An A-type monoamine oxidase inhibitor comprising, as an active ingredient, an isoxazole derivative which is a furyl group, a 3-furyl group, a 2-thienyl group, or a 3-thienyl group, or a pharmaceutically acceptable salt thereof. 8. The method according to claim 1, wherein R ¹ is a phenyl group, 2
-Chlorophenyl group, 4-chlorophenyl group, 2,4-
Difluorophenyl group, 2,4-dichlorophenyl group,
A isocyanate derivative which is a 2-furyl group or a 2-thienyl group or a pharmaceutically acceptable salt thereof as an active ingredient
Type monoamine oxidase inhibitors. 9. The method according to claim 1, wherein R ² is a hydrogen atom, a halogen atom, C ₁ -C _6.
Alkyl group, fluoromethyl group, difluoromethyl group,
Trifluoromethyl group, 2-fluoroethyl group, 1-chloroethyl group, 2-chloroethyl group, 2,2,2-trifluoroethyl group, methoxymethyl group, methoxyethyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, 2-cyclopentenyl group, 3-cyclopentenyl group, 2-cyclohexenyl group, 3-cyclohexenyl group, a methoxy group, an ethoxy group, a cyano group, a carboxy Group, formyl group, acetyl group, methoxycarbonyl group,
An A-type monoamine oxidase inhibitor comprising, as an active ingredient, an isoxazole derivative which is an ethoxycarbonyl group, a carbamoyl group, a methylcarbamoyl group, an ethylcarbamoyl group or an N, N-dimethylcarbamoyl group, or a pharmaceutically acceptable salt thereof. 10. The method according to claim 1, wherein R ² is a hydrogen atom, a halogen atom, C ₁ -C
₆ alkyl group, C ₂ -C ₆ alkenyl group or C ₂ -C ₆
An A-type monoamine oxidase inhibitor comprising, as an active ingredient, an isoxazole derivative which is an alkynyl group or a pharmaceutically acceptable salt thereof. 11. The method according to claim 1, wherein R ² is a hydrogen atom, a halogen atom, C ₁ -C
₍₄₎ An A-type monoamine oxidase inhibitor comprising, as an active ingredient, an isoxazole derivative which is an alkyl group, an allyl group, an isopropenyl group, a 2-butenyl group or a propargyl group, or a pharmaceutically acceptable salt thereof. 12. The method according to claim 1, wherein R ² is a hydrogen atom, a chlorine atom, an ethyl group, an propyl group, an isopropyl group, an isobutyl group or a t-butyl group. An A-type monoamine oxidase inhibitor comprising an isoxazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient. 13. A type according to claim 1, wherein R ² is a hydrogen atom or an isopropyl group, or a pharmacologically acceptable salt thereof as an active ingredient. Monoamine oxidase inhibitors. 14. The method according to claim 1, wherein R ³ is an amino group, a mono C ₁ -C ₆ alkylamino group, a di (C ₁ -C ₆ alkyl) amino group. Or 1
Is a 5- or 6-membered saturated heterocyclic group which contains one nitrogen atom and may further contain one nitrogen atom or oxygen atom, provided that the group is bonded on the nitrogen atom, or an isoxazole derivative thereof. An A-type monoamine oxidase inhibitor comprising a pharmacologically acceptable salt as an active ingredient. 15. The method according to claim 1, wherein R ³ is an amino group, a methylamino group, an ethylamino group, an N, N-dimethylamino group, a piperidyl group or a morpholinyl group. A-type monoamine oxidase inhibitor comprising an isoxazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient. 16. A method according to claim 1, wherein R ³ is an amino group, an isoxazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient. medicine. 17. An A-type monoamine oxidase inhibitor comprising, as an active ingredient, an isoxazole derivative wherein X is an oxygen atom or a pharmacologically acceptable salt thereof, according to one of claims 1 to 16. 18. An A-type monoamine oxidase inhibitor comprising an isoxazole derivative wherein n is 2 or a pharmacologically acceptable salt thereof as an active ingredient, according to one of claims 1 to 17. 20. 3- (2-aminoethoxy) -5-phenylisoxazole, 3- (2-aminoethoxy) -4-chloro-5-phenylisoxazole, 3- (2-aminoethoxy)- 4-ethyl-5-phenylisoxazole, 3- (2-aminoethoxy) -5-phenyl-4-propylisoxazole, 3- (2-aminoethoxy) -4-isopropyl-5-
Phenylisoxazole, 3- (2-aminoethoxy) -4-isobutyl-5-phenylisoxazole, 3- (2-aminoethoxy) -5- (2-chlorophenyl) -4-isopropylisoxazole, 3 -(2-aminoethoxy) -5- (4-chlorophenyl) isoxazole, 3- (2-aminoethoxy) -5- (4-chlorophenyl) -4-isopropylisoxazole, 3- (2-aminoethoxy)- 5- (2,4-dichlorophenyl) -4-isopropylisoxazole, 3- (2-aminoethoxy) -5- (2-furyl) -4
-Isopropylisoxazole, 3- (2-aminoethoxy) -5- (2-thienyl) isoxazole, 3- (2-aminoethoxy) -4-chloro-5- (2-
Thienyl) isoxazole, 3- (2-aminoethoxy) -4-isopropyl-5-
A-type monoamine oxidase inhibitor comprising (2-thienyl) isoxazole or 4-allyl-3- (2-aminoethoxy) -5-phenylisoxazole or a pharmaceutically acceptable salt thereof as an active ingredient. (20) A therapeutic or prophylactic agent for depression, comprising the isoxazole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (19) as an active ingredient.